Patent application title: PHARMACEUTICAL FORMULATION
Inventors:
Mike Tso-Ping Li (Cupertino, CA, US)
Assignees:
KAI Pharmaceuticals, Inc.
IPC8 Class: AA61K4726FI
USPC Class:
424 945
Class name: Drug, bio-affecting and body treating compositions enzyme or coenzyme containing transferases (2. ), lyase (4.), isomerase (5.), ligase (6.)
Publication date: 2014-01-23
Patent application number: 20140023632
Abstract:
A pharmaceutical formulation for a PKC modulatory peptide and a transport
moiety comprising the aforementioned components and an anti-aggregant.Claims:
1. An aqueous solution comprising, 0.25 mg/mL to 5.0 mg/mL of a conjugate
comprising a PKC modulatory peptide linked to a transport peptide via a
disulfide bond, wherein the PKC modulatory peptide comprises the amino
acid sequence SFNSYELGSL (SEQ ID NO:34), 2.0 mg/mL to 50 mg/mL of an
anti-aggregant sugar, and water for injection.
2. The solution of claim 1, wherein the anti-aggregant sugar is selected from the group consisting of mannitol, fructose, sucrose and glycerol.
3. The solution of claim 1, wherein the conjugate is KAI-9803.
4. The solution of claim 3, wherein the anti-aggregant sugar is mannitol.
5. An aqueous solution comprising, 0.1 mg/mL to 10 mg/mL of a conjugate comprising a PKC modulatory peptide linked to a transport peptide via a disulfide bond, wherein the PKC modulatory peptide comprises the amino acid sequence SFNSYELGSL (SEQ ID NO:34), 5.0 mg/mL to 40 mg/mL of an anti-aggregant sugar, and water for injection.
6. The solution of claim 5, wherein the anti-aggregant sugar is selected from the group consisting of mannitol, fructose, sucrose and glycerol.
7. The solution of claim 5, wherein the conjugate is KAI-9803.
8. The solution of claim 7, wherein the anti-aggregant sugar is mannitol.
9. An aqueous solution comprising, 2.0 mg/mL to 3.0 mg/mL of a conjugate comprising a PKC modulatory peptide linked to a transport peptide via a disulfide bond, wherein the PKC modulatory peptide comprises the amino acid sequence SFNSYELGSL (SEQ ID NO:34), 15 mg/mL to 25 mg/mL of an anti-aggregant sugar, and water for injection.
10. The solution of claim 9, wherein the anti-aggregant sugar is selected from the group consisting of mannitol, fructose, sucrose and glycerol.
11. The solution of claim 9, wherein the conjugate is KAI-9803.
12. The solution of claim 11, wherein the anti-aggregant sugar is mannitol.
13. An aqueous solution comprising, 0.5 mg/mL to 5.0 mg/mL of a conjugate comprising a PKC modulatory peptide linked to a transport peptide via a disulfide bond, wherein the PKC modulatory peptide comprises the amino acid sequence SFNSYELGSL (SEQ ID NO:34), 10.0 mg/mL to 30.0 mg/mL of an anti-aggregant sugar, and water for injection.
14. The solution of claim 13, wherein the anti-aggregant sugar is selected from the group consisting of mannitol, fructose, sucrose and glycerol.
15. The solution of claim 13, wherein the conjugate is KAI-9803.
16. The solution of claim 15, wherein the anti-aggregant sugar is mannitol.
17. An aqueous solution comprising, 2.0 mg/mL to 3.0 mg/mL of a conjugate comprising a PKC modulatory peptide linked to a transport peptide via a disulfide bond, wherein the PKC modulatory peptide comprises the amino acid sequence SFNSYELGSL (SEQ ID NO:34), 15.0 mg/mL to 25.0 mg/mL of an anti-aggregant sugar, and water for injection.
18. The solution of claim 17, wherein the anti-aggregant sugar is selected from the group consisting of mannitol, fructose, sucrose and glycerol.
19. The solution of claim 17, wherein the conjugate is KAI-9803.
20. The solution of claim 19, wherein the anti-aggregant sugar is mannitol.
Description:
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 12/764,856, filed on Apr. 21, 2010, now allowed, which is a continuation of U.S. patent application Ser. No. 11/849,929, filed on Sep. 4, 2007, now U.S. Pat. No. 7,727,958, issued Jun. 1, 2010, which is a divisional of U.S. patent application Ser. No. 11/240,962, filed Sep. 30, 2005, now U.S. Pat. No. 7,265,092, issued Sep. 4, 2007, which claims the benefit of priority of U.S. Provisional Patent Application No. 60/615,486 filed Sep. 30, 2004. The contents of each application listed in this paragraph are fully incorporated by reference herein for all purposes.
REFERENCE TO SEQUENCE LISTING SUBMITTED VIA EFS-WEB
[0002] The entire content of the following electronic submission of the sequence listing via the USPTO EFS-WEB server, as authorized and set forth in MPEP §1730 II.B.2(a)(C), is incorporated herein by reference in its entirety for all purposes. The sequence listing is identified on the electronically filed text file as follows:
TABLE-US-00001 File Name Date of Creation Size (bytes) 0915088005US03seqlist.txt August 29, 2013 89,213 bytes
TECHNICAL FIELD
[0003] This invention relates to pharmaceutical formulations, particularly to formulations of amino acids, peptides and small proteins, and specifically to formulations for PKC peptide/transporter conjugates.
BACKGROUND ART
[0004] Protein kinase C ("PKC") is a key enzyme in signal transduction involved in a variety of cellular functions, including cell growth, regulation of gene expression, and ion channel activity. The PKC family of isozymes includes at least 10 different protein kinases that can be divided into at least three subfamilies based on their homology and sensitivity to activators. (See the drawing FIGURE.) Each isozyme includes a number of homologous ("conserved" or "C") domains interspersed with isozyme-unique ("variable" or "V") domains. Members of the "classical" subfamily, α (SEQ ID NO:164), βI (SEQ ID NO:165), βII (SEQ ID NO:166) and γPKC (SEQ ID NO:167), contain four homologous domains (C1, C2, C3 and C4) and require calcium, phosphatidylserine, and diacylglycerol or phorbol esters for activation. Members of the "novel" subfamily, δ (SEQ ID NO:168), ε (SEQ ID NO:169), η (SEQ ID NO:170) and θPKC (SEQ ID NO:171), lack the C2 homologous domain and do not require calcium for activation. Finally, members of the "atypical" subfamily, ζ (SEQ ID NO:173) and λ/PKC (SEQ ID NO:172), lack both the C2 and one-half of the C1 homologous domains and are insensitive to diacylglycerol, phorbol esters and calcium.
[0005] Individual isozymes of PKC have been implicated in the mechanisms of various disease states, including the following: cancer (alpha and delta PKC); cardiac hypertrophy and heart failure (beta I and beta II PKC) nociception (gamma and epsilon PKC); ischemia including myocardial infarction (delta and epsilon PKC); immune response, particularly T-cell mediated (theta PKC); and fibroblast growth and memory (zeta PKC).
DISCLOSURE OF THE INVENTION
[0006] In accordance with the objects outlined above, the disclosed invention provides a pharmaceutical formulation for a protein kinase C modulatory peptide and a cationic (i.e., positively charged) transport peptide and an anti-aggregant. A preferred anti-aggregant is a sugar characterized by having a sufficient number stereochemically aligned hydroxyl moieties to interact with the modulatory peptide and/or the transport peptide hydrophobic and/or positively charged portions so as to favor their organization with the anti-aggregant, rather than aggregation with each other. PKC modulatory peptides, such as peptides derived from various PKC variable regions, comprise preferred embodiments. Cationic transport moieties useful in the invention include cationic peptides, such as poly-arginine and HIV-tat. A particularly preferred embodiment comprises a PKC inhibitory peptide and a HIV-tat derived transport peptide. An example of such an embodiment is KAI-9803 (SEQ ID NO:1).
[0007] In one of the particular aspects of the above-described pharmaceutical formulation, the ratio of anti-aggregant to peptide/transporter conjugate ranges from about 100:1 to about 1:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, and 1:1.
[0008] Another aspect of the invention provides a stable pharmaceutical product for shipping and storing prior to use, including a lyophilized cake of KAI-9803 and an anti-aggregant in a sealed container. The lyophilized product is preferably obtained from a solution of KAI-9803 plus acetate counterion. The ratio of KAI-9803 to anti-aggregant is from about 1:5 to about 1:100, particularly about 1:80 and especially about 1:8. The anti-aggregant is preferably a sugar. One specific such product is 5 mg KAI-9803 and 40 mg mannitol in a stoppered glass vial. Instructions for reconstitution are preferably incorporated on the container or its attached label, outer packaging and/or package insert.
[0009] Another aspect of the invention provides a formulation for parenteral (particularly intracoronary) administration that is about 2.5 mg/mL KAI-9803 and about 20 mg/mL mannitol reconstituted from a lyophilized cake using sodium chloride for injection, USP (preferably 0.9%) to a concentration ranging from about 0.001 to 2.5 mg/mL, preferably about 0.01 to 1.0 mg/mL. To reconstitute the lyophilized formulation for administration, a sealed container of product is first warmed to about room temperature, after which a pharmaceutically acceptable solvent (such as saline, preferably 9% saline) is added in an amount sufficient to solubilize the lyophilized cake, followed by the addition of such additional quantity of solvent as is necessary to obtain a desired concentration for administration.
[0010] Still another aspect of the invention is a method of manufacture, including the steps:
[0011] (A) Appropriate amounts of anti-aggregant, hydrophobic active agent and/or cationic transport moiety are introduced to a suitably sized container (preferably a glass vial) as dry solids.
[0012] (B) A pharmaceutically acceptable solvent is added to the container in an amount sufficient to dissolve the solids.
[0013] (C) The solution thus-formed is lyophilized to dryness.
[0014] (D) The container is sealed (optionally after first filling the head-space with a non-reactive gas, such as nitrogen).
[0015] Other aspects and embodiments will be apparent to those skilled in the art form the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The drawing FIGURE shows a schematic of the three families of protein kinase C isozymes.
MODES OF CARRYING OUT THE INVENTION
[0017] The presently described invention relates to pharmaceutical formulations of peptides which modulate the activity of one or more protein kinase C isozymes. In certain embodiments, the peptides discussed herein are coupled to a carrier moiety to facilitate transport of the modulatory peptide to a target cell. Typically, preferred embodiments of the disclosed pharmaceutical formulations further comprise an anti-aggregant and one or more excipients. The pharmaceutical formulations comprising the modulatory peptides provide advantages in the handling of the active pharmaceutical ingredients, in formulation manufacture, stability, concentration and ease of use. These and other advantages are described in greater detail below.
DEFINITIONS
[0018] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
[0019] A "PKC modulatory peptide" or "a peptide which modulate the activity of one or more protein kinase C isozymes" refer to a peptide that can promote, enhance or activate one or more PKC isozymes, or alternatively the peptide can also inhibit or inactivate one or more PKC isozymes.
[0020] The term "API" means active pharmaceutical ingredient, which as used herein refers to a PKC modulatory peptide and a transport moiety, covalently bound to one another, and/or one or more active agents.
[0021] The term "disorder" or "disease state" means any mammalian disease, condition, symptom, or indication, preferably arising in a human patient.
[0022] The term "effective amount" refers to that amount of an API that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment.
[0023] The term "KAI-9803" refers to an peptide derived from the first variable region of δSPKC conjugated via a Cys-Cys disulfide linkage to a HIV Tat-derived transporter peptide, and can be represented as follows:
##STR00001##
[0024] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where such event or circumstance occurs and instances in which it does not.
[0025] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions.
[0026] The term "pharmaceutically acceptable salt" or "counterion" refers to salts which retain the biological effectiveness and properties of the API and which are not biologically or otherwise undesirable. In many cases, the API will be capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable base addition salts can be prepared from inorganic and/or organic bases. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and/or organic acids. For example, inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0027] The term "pharmaceutical product" refers to an API, formulated and filled into a container for storage, transportation, or administration.
[0028] The term "PKC-derived peptide" refers to a PKC isozyme- and/or variable region-specific peptides as described, for example, in U.S. Pat. Nos. 5,783,405, 6,165,977, US2002/0150984, US2002/0168354, US2002/057413, US2003/0223981, US2004/0009922 and in copending U.S. provisional application Ser. No. 60/550,755, filed Mar. 5, 2004, all of which are hereby incorporated by reference in their entirety.
[0029] The term "transporter moiety" means a component of an API that facilitates cellular uptake, such as cationic polymers, peptides and antibody sequences, including polylysine, polyarginine, Antennapedia-derived peptides, HIV Tat-derived peptides and the like. An example of a transporter moiety is a "transporter peptide", which is a peptide which facilitates cellular uptake of a PKC modulating peptide which is chemically associated or bonded to the transporter peptide.
[0030] The term "treatment" or "treating" means any treatment of a disease or disorder in a mammal, including: preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop; inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and/or relieving the disease or disorder, that is, causing the regression of clinical symptoms.
[0031] The term "prophylaxis" is intended as an element of "treatment" to encompass both "preventing" and "suppressing" as defined herein. It will be understood by those skilled in the art that in human medicine it is not always possible to distinguish between "preventing" and "suppressing" since the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events.
Protein Kinase C Modulatory Peptides
[0032] Various PKC isozyme- and variable region-specific peptides have been described and can be used with the presently disclosed invention. Preferably, the PKC modulatory peptide is a V1, V3 or VS-derived peptide. The following US patents or patent applications describe a variety of suitable peptides that can be used with the presently disclosed invention: U.S. Pat. Nos. 5,783,405, 6,165,977, 6,855,693, US2004/0204364, US2002/0150984, US2002/0168354, US2002/057413, US2003/0223981, US2004/0009922 and Ser. No. 10/428,280, each of which are incorporated herein by reference in their entirety. Table 1 provides a listing of preferred PKC modulatory peptides for use with the present invention.
TABLE-US-00002 TABLE 1 Peptides derived from PKC isozymes Peptide SEQ ID NO. Sequence αV3-1 SEQ ID NO: 2 I-P-E-G-D-E-E-G αV5-1 SEQ ID NO: 3 Q-L-V-I-A-N αV5-1.1 SEQ ID NO: 4 G-L-G-A-E-N αV5-1.2 SEQ ID NO: 5 A-R-G-A-E-N αV5-1.3 SEQ ID NO: 6 C-G-K-G-A-E-N αV5-1.4 SEQ ID NO: 7 C-G-K-G-A-E-N βC2-1 SEQ ID NO: 8 K-Q-K-T-K-T-I-K βc2-2 SEQ ID NO: 9 M-D-P-N-G-L-S-D-P-Y-V- K-L βC2-3 SEQ ID NO: 10 I-P-D-P-K-S-E βC2-4 SEQ ID NO: 11 S-L-N-P-E-W-N-E-T βV3-1 SEQ ID NO: 12 V-P-P-E-G-S-E-A βIV5-1 SEQ ID NO: 13 K-L-F-I-M-N βIV5-2 SEQ ID NO: 14 R-D-K-R-D-T-S βIV5-2.1 SEQ ID NO: 15 C-A-R-D-K-R-D-T-S βIV5-2.2 SEQ ID NO: 16 G-R-D-K-R-D-T-S βIV5-2.3 SEQ ID NO: 17 A-R-D-K-R-D-T-S βIV5-3 SEQ ID NO: 18 A-R-D-K-R-D-T-S-N-F-D-K βIV5-4 SEQ ID NO: 19 A-G-F-S-Y-T-N-P-E-F-V- I-N-V βIIV5-1 SEQ ID NO: 20 Q-E-V-I-R-N βIIV5-2 SEQ ID NO: 21 C-G-R-N-A-E βIIV5-3 SEQ ID NO: 22 A-C-G-R-N-A-E βIIV5-3.1 SEQ ID NO: 23 A-C-G-K-N-A-E βIIV5-4 SEQ ID NO: 24 K-A-C-G-R-N-A-E βIIV5-5 SEQ ID NO: 25 C-G-R-N-A-E-N βIIV5-6 SEQ ID NO: 26 A-C-G-R-N-A-E βIIV5-7 SEQ ID NO: 27 S-F-V-N-S-E-F-L-K-P-E- V-L-S γV3-1 SEQ ID NO: 28 V-A-D-A-D-N-C-S γV5-1 SEQ ID NO: 29 G-R-S-G-E-N γV5-1.1 SEQ ID NO: 30 G-L-S-G-E-N γV5-2 SEQ ID NO: 31 R-L-V-L-A-S γV5-3 SEQ ID NO: 32 P-C-G-R-S-G-E-N δV1-1 SEQ ID NO: 33 C-S-F-N-S-Y-E-L-G-S-L δV1-1.1 SEQ ID NO: 34 S-F-N-S-Y-E-L-G-S-L δV1-1.2 SEQ ID NO: 35 T-F-N-S-Y-E-L-G-S-L δV1-1.3 SEQ ID NO: 36 A-F-N-S-N-Y-E-L-G-S-L δV1-1.4 SEQ ID NO: 37 S-F-N-S-Y-E-L-G-T-L δV1-1.5 SEQ ID NO: 38 S-T-N-S-Y-E-L-G-S-L δV1-1.6 SEQ ID NO: 39 S-F-N-S-F-E-L-G-S-L δV1-1.7 SEQ ID NO: 40 S-N-S-Y-D-L-G-S-L δV1-1.8 SEQ ID NO: 41 S-F-N-S-Y-E-L-P-S-L δV1-1.9 SEQ ID NO: 42 T-F-N-S-Y-E-L-G-T-L δV1-1.10 SEQ ID NO: 43 S-F-N-S-Y-E-I-G-S-V δV1-1.11 SEQ ID NO: 44 S-L-N-S-Y-E-V-G-S-I δV1-1.12 SEQ ID NO: 45 S-F-N-S-Y-E-L-G-S-V δV1-1.13 SEQ ID NO: 46 S-F-N-S-Y-E-L-G-S-I δV1-1.14 SEQ ID NO: 47 S-F-N-S-Y-E-I-G-S-L δV1-1.15 SEQ ID NO: 48 S-F-N-S-Y-E-V-G-S-L δV1-1.16 SEQ ID NO: 49 A-F-N-S-Y-E-L-G-S-L δV1-1.17 SEQ ID NO: 50 Y-D-L-G-S-L δV1-1.18 SEQ ID NO: 51 F-D-L-G-S-L δV1-1.19 SEQ ID NO: 52 Y-D-I-G-S-L δV1-1.20 SEQ ID NO: 53 Y-D-V-G-S-L δV1-1.21 SEQ ID NO: 54 Y-D-L-P-S-L δV1-1.22 SEQ ID NO: 55 Y-D-L-G-L-L δV1-1.23 SEQ ID NO: 56 Y-D-L-G-S-I δV1-1.24 SEQ ID NO: 57 Y-D-L-G-S-V δV1-1.25 SEQ ID NO: 58 I-G-S-L δV1-1.26 SEQ ID NO: 59 V-G-S-L δV1-1.27 SEQ ID NO: 60 L-P-S-L δV1-1.28 SEQ ID NO: 61 L-G-L-L δV1-1.29 SEQ ID NO: 62 L-G-S-I δV1-1.30 SEQ ID NO: 63 L-G-S-V δV1-2 SEQ ID NO: 64 A-L-S-T-E-R-G-K-T-L-V δV1-2.1 SEQ ID NO: 65 A-L-S-T-D-R-G-K-T-L-V δV1-2.2 SEQ ID NO: 66 A-L-T-S-D-R-G-K-T-L-V δV1-2.3 SEQ ID NO: 67 A-L-T-T-D-R-G-K-S-L-V δV1-2.4 SEQ ID NO: 68 A-L-T-T-D-R-P-K-T-L-V δV1-2.5 SEQ ID NO: 69 A-L-T-T-D-R-G-R-T-L-V δV1-2.6 SEQ ID NO: 70 A-T-T-T-D-K-G-K-T-L-V δV1-2.7 SEQ ID NO: 71 A-L-T-T-D-K-G-K-T-L-V δV1-3 SEQ ID NO: 72 V-L-M-R-A-A-E-E-P-V δV1.4 SEQ ID NO: 73 Q-S-M-R-S-E-D-E-A-K δV1.5 SEQ ID NO: 163 A-F-N-S-Y-E-L-G-S δV3-1 SEQ ID NO: 74 Q-G-F-E-K-K-T-G-V δV3-2 SEQ ID NO: 75 D-N-N-G-T-Y-G-K-I δV5-1 SEQ ID NO: 76 K-N-L-I-D-S δV5-2 SEQ ID NO: 77 V-K-S-P-R-D-Y-S δV5-2.1 SEQ ID NO: 78 V-K-S-P-C-R-D-Y-S δV5-2.2 SEQ ID NO: 79 I-K-S-P-R-L-Y-S δV5-3 SEQ ID NO: 80 K-N-L-I-D-S δV5-4 SEQ ID NO: 81 P-K-V-K-S-P-R-D-Y-S-N εV1-1 SEQ ID NO: 82 N-G-L-L-K-I-K εV1-2 SEQ ID NO: 83 E-A-V-S-L-K-P-T εV1-3 SEQ ID NO: 84 L-A-V-F-H-D-A-P-I-G-Y εV1-4 SEQ ID NO: 85 D-D-F-V-A-N-C-T-I εV1-5 SEQ ID NO: 86 W-I-D-L-E-P-E-G-R-V εV1-6 SEQ ID NO: 87 H-A-V-G-P-R-P-Q-T-F εV1-7 SEQ ID NO: 88 N-G-S-R-H-F-E-D εV1-7.1 SEQ ID NO: 89 H-D-A-P-I-G-D-Y εV1-7.2 SEQ ID NO: 90 H-D-A-P-I-G εV1-7.3 SEQ ID NO: 91 H-D-A-A-I-G-Y-D εV1-7.4 SEQ ID NO: 92 H-D-A-P-I-P-Y-D εV1-7.5 SEQ ID NO: 93 H-N-A-P-I-G-Y-D εV1-7.6 SEQ ID NO: 94 H-A-A-P-I-G-D εV1-7.7 SEQ ID NO: 95 A-D-A-P-I-G-Y-D εV1-7.8 SEQ ID NO: 96 H-D-A-P-A-G-Y-D εV1-7.9 SEQ ID NO: 97 H-D-A-P-I-G-A-D εV-7.10 SEQ ID NO: 98 H-D-A-P-I-A-Y-D εV1-7.11 SEQ ID NO: 99 H-D-A-P-I-G-Y-A εV3-1 SEQ ID NO: 100 S-S-P-S-E-E-D-R-S εV3-2 SEQ ID NO: 101 P-C-D-Q-E-I-K-E εV3-3 SEQ ID NO: 102 E-N-N-I-R-K-A-L-S εV3-4 SEQ ID NO: 103 G-E-V-R-Q-G-Q-A εV5-1 SEQ ID NO: 104 E-A-I-V-K-Q εV5-2 SEQ ID NO: 105 I-K-T-K-R-D-V εV5-2.1 SEQ ID NO: 106 I-K-T-K-R-L-I εV5-3 SEQ ID NO: 107 C-E-A-I-V-K-Q εV5-4 SEQ ID NO: 108 T-K-R-D-V-N-N-F-D-Q ζV1-1 SEQ ID NO: 109 V-R-L-K-A-H-Y ζV1-2 SEQ ID NO: 110 V-D-S-E-G-D ζV1-3 SEQ ID NO: 111 V-F-P-S-I-P-E-Q ζV3-1 SEQ ID NO: 112 S-Q-E-P-P-V-D-D-K-N-E- D-A-D-L ζV3-2 SEQ ID NO: 113 I-K-D-D-S-E-D ζV3-3 SEQ ID NO: 114 P-V-I-D-G-M-D-G-1 ζV5-1 SEQ ID NO: 115 E-D-A-I-K-R ζV5-1.1 SEQ ID NO: 116 E-D-A-I-R ζV5-2 SEQ ID NO: 117 I-T-D-D-Y-G-L-D ζV5-2.1 SEQ ID NO: 118 I-T-D-D-Y-G-D-L ζV5-3 SEQ ID NO: 119 D-D-Y-G-L-D-N ηV1-1 SEQ ID NO: 120 N-G-Y-L-R-V-R ηV1-2 SEQ ID NO: 121 E-A-V-G-L-Q-P-T
ηV1-3 SEQ ID NO: 122 L-A-V-F-H-E-T-P-L-G-Y ηV1-4 SEQ ID NO: 123 D-F-V-A-N-C-T-L ηV1-5 SEQ ID NO: 124 W-V-D-L-E-P-E-G-K-V ηV1-6 SEQ ID NO: 125 H-S-L-F-K-K-G-H ηV1-7 SEQ ID NO: 126 T-G-A-S-D-T-F-E-G ηV5-1 SEQ ID NO: 127 E-G-H-L-P-M ηV5-1.1 SEQ ID NO: 128 E-G-H-D-P-M ηV5-2 SEQ ID NO: 129 I-K-S-R-E-D-V-S ηV5-3 SEQ ID NO: 130 V-R-S-R-E-D-V-S ηV5-4 SEQ ID NO: 131 P-R-I-K-S-R-E-D-V λV1-1 SEQ ID NO: 132 H-Q-V-R-V-K-A-Y-Y-R λV1-2 SEQ ID NO: 133 Y-E-L-N-K-D-S-E-L-L-I λV3-1 SEQ ID NO: 134 M-D-Q-S-S-M-H-S-D-H-A- Q-T-V-I λV3-2 SEQ ID NO: 135 L-D-Q-V-G-E-E λV3-3 SEQ ID NO: 136 E-A-M-N-T-R-E-S-G λV5-1 SEQ ID NO: 137 D-D-I-V-R-K μV5-2 SEQ ID NO: 138 V-K-L-C-D-F-G-F μV5-2.1 SEQ ID NO: 139 I-R-L-C-D-F-A-F μV5-3 SEQ ID NO: 140 Q-V-K-L-C-D-F-G-F-A μV1-1 SEQ ID NO: 141 M-S-V-P-P-L-L-R-P μV1-2 SEQ ID NO: 142 K-F-P-E-C-G-F-Y-G-L-Y μV3-1 SEQ ID NO: 143 D-P-D-A-D-Q-E-D-S μV3-2 SEQ ID NO: 144 S-K-D-T-L-R-K-R-H μV3-3 SEQ ID NO: 145 I-T-L-F-Q-N-D-T-G μV3-4 SEQ ID NO: 146 G-S-N-S-H-K-D-I-S μV5-1 SEQ ID NO: 147 S-D-S-P-E-A ΘV1-1 SEQ ID NO: 148 G-L-S-N-F-D-C-G ΘV1-2 SEQ ID NO: 149 Y-V-E-S-E-N-G-Q-M-Y-I ΘV1-3 SEQ ID NO: 150 I-V-K-G-K-N-V-D-L-I ΘV1-4 SEQ ID NO: 151 D-M-N-E-F-E-T-E-G-F ΘV3-1 SEQ ID NO: 152 C-S-I-K-N-E-A-R-L ΘV3-2 SEQ ID NO: 153 G-K-R-E-P-Q-G-I-S ΘV3-3 SEQ ID NO: 154 D-E-V-D-K-M-C-H-L ΘV5-1 SEQ ID NO: 155 R-A-L-I-N-S ΘV5-2 SEQ ID NO: 156 V-K-S-P-F-D-C-S ΘV5-2.1 SEQ ID NO: 157 V-R-S-P-F-D-C-S ΘV5-3 SEQ ID NO: 158 D-R-A-L-I-N-S V5-1 SEQ ID NO: 159 I-S-G-E-F-G-L-D V5-1.1 SEQ ID NO: 160 C-S-G-E-F-G-L-D V5-2 SEQ ID NO: 161 D-D-D-I-V-R-K V5-3 SEQ ID NO: 162 D-D-I-V-R-K
[0033] As discussed more fully below, it is preferable that the PKC modulatory peptide be chemically associated with a transport peptide. In a particularly preferred embodiment, the modulatory peptide and the transport peptide are linked via a disulfide bond. In the case of the forming a disulfide bond, it may be advantageous to add Cys residue to the PKC modulatory peptide sequence, preferably at the amino terminus of the peptide. Alternatively, an endogenous Cys residue can be exploited to link the modulatory peptide with the transport peptide or moiety. Methods of forming disulfide bonds are well known to those of ordinary skill in the art, for example mixing components in a reducing environment and then introducing the components to an oxidizing environment.
Transport Peptide
[0034] A wide variety of molecules (particularly macromolecules such as peptides) intended for cellular uptake were found to be transported poorly across cell membranes. Among the solutions proposed to facilitate cellular uptake have been the use of transporter moieties such as cationic (i.e., positively charged) polymers, peptides and antibody sequences, including polylysine, polyarginine, Antennapedia-derived peptides, HIV Tat-derived peptides and the like. (See, for example, U.S. Pat. Nos. 4,847,240, 5,652,122, 5,670,617, 5674,980, 5,747,641, 5,804,604, 5,888,762, 6,316,003, 6,593,292, US2003/0104622, US2003/0199677 and US2003/0206900, all of which are hereby incorporated by reference in their entirety.)
[0035] A particular example of a peptide/transporter conjugate is KAI-9803 (SEQ ID NO:1), which is made up of a δSPKC-derived peptide and a HIV Tat-derived transporter peptide. It is currently being developed for human therapeutic use in the treatment of reperfusion injury. As with most pharmaceutical active agents, KAI-9803 is prepared as a pharmaceutical formulation with certain stability, tolerability and bioavailability requirements.
Excipients and Anti-Aggregants
[0036] Pharmaceutically acceptable excipients suitable for use as carriers or diluents are well known in the art, and may be used in a variety of formulations. See, e.g., Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, Editor, Mack Publishing Company (1990); Remington: The Science and Practice of Pharmacy, 20th Edition, A. R. Gennaro, Editor, Lippincott Williams & Wilkins (2000); Handbook of Pharmaceutical Excipients, 3rd Edition, A. H. Kibbe, Editor, American Pharmaceutical Association, and Pharmaceutical Press (2000); and Handbook of Pharmaceutical Additives, compiled by Michael and Irene Ash, Gower (1995).
[0037] Lyophilized formulations are typically prepared from an active agent dissolved in a pharmaceutically acceptable solvent, optionally including excipients such as bulking agents, solubility enhancers, pH buffers and the like. The solution is subjected to reduced temperatures and pressure to drive off the liquids, leaving a solid cake that can be stored for future use.
[0038] The lyophilized formulations of the disclosed invention advantageously include an anti-aggregant, such as a sugar, where such sugars are sufficient to interact with the active agents' hydrophobic and/or positively charged portions to favor their organization with the sugar, rather than aggregation with each other. Suitable anti-aggregant sugars include fructose, lactose, glycerol, mannitol and D-mannose, preferably mannitol.
[0039] The transport moieties used to facilitate cellular uptake of peptides (such as the δPKC, sequence portion of KAI-9803) share certain attributes (generally being cationic) that contribute to their functionality in vivo, but have been discovered to give rise to the formation of aggregates under lyophilized storage conditions. The modulatory peptides may also possess structural features which facilitate the formation of aggregates. While not wishing to be bound to any particular theory, such aggregation may result from peptide dimerization and a tendency for the peptides to "organize" into aggregates.
[0040] The formation of a detrimental level of aggregates interferes with re-dissolution of peptides and peptide conjugates, in turn interfering with administration where the possibility of particulates would be unacceptable for certain routes of administration (e intracoronary). Notwithstanding these drawbacks, the creation of a detrimental level of aggregates in the formulation complicates determining final concentration in that the precise amount of peptide dissolved per unit of liquid. Such a determination cannot be accurately calculated without first determining and then subtracting the weight of undissolved material. Unacceptable levels of aggregation can result in from 0.1 to 50% aggregation of the peptide conjugates. Thus, another aspect of the present invention pertains to the incorporation of an anti-aggregant in lyophilized formulations of peptides or peptide/transporter conjugates. In addition to suppressing the formation of aggregants in the lyophilized product, certain anti-aggregants can enhance the stabilization of the pharmaceutical formulation.
Administration
[0041] Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly, intraperitoneal, intravenously, and in the case of the present invention via intracoronary injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid (e.g., dried or lyophilized) forms suitable for reconstitution into solution or suspension in liquid prior to injection, or as emulsions. Generally, suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, minor amounts of non-toxic auxiliary substances can be employed, such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, tonicifiers and the like including, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc. Dosage forms for intravenous (IV) administration generally comprise an active agent incorporated into a sterile solution of simple chemicals such as sugars, amino acids or electrolytes, which can be easily carried by the circulatory system and assimilated. Such solutions are typically prepared with saline or buffer. The pH of such IV fluids may vary, and will typically be from 3.5 to 8.0, as known in the art.
[0042] The intracoronary injection formulations of the disclosed invention are typically prepared using sodium chloride for injection, USP (preferably 0.9%) for reconstitution of the Lyophilized API into solution at concentrations ranging from 0.001 to 2.5 mg/mL, preferably 0.01 to 1.0 mg/mL.
Exemplary Formulations
[0043] The pharmaceutical formulations of the disclosed invention preferably include a PKC modulatory peptide, a transport peptide, and an anti-aggregant agent. Typically, the PKC modulatory peptide and the transport peptide are chemically associated with one another. For example, it is preferred that the modulatory peptide and the transport peptide are covalently bonded to one another. In a preferred embodiment, the PKC modulatory peptide and the transport peptide are linked via a disulfide bond.
[0044] In a pre-lyophilized embodiment of the invention, the formulation further includes a sufficient amount of a pharmaceutically acceptable solvent (preferably water for injection, USP) to solubilize the foregoing components. A lyophilized embodiment of the invention includes components described above in the form of a solid cake.
[0045] The ratio of peptides to anti-aggregant in the disclosed formulations ranges from about 100:1 to about 5:1, preferably from about 80:1 to about 5:1, more preferably from about 80:1 to about 8:1; the actual ratio will depend upon the identity of the components and the concentration desired for the lyophilized and/or reconstituted drug products.
[0046] One aspect of the present invention provides a pre-lyophilized formulation for a peptide or peptide/transporter conjugate, as follows:
TABLE-US-00003 TABLE 2 Ingredient Amount (wt/vol) API 0.25 to 5.0 mg/mL Anti-aggregant Sugar 2.0 to 50.0 mg/mL WFI (USP) q.s. to 100
[0047] and the lyophilized product therefrom.
[0048] Another aspect of the preferred peptide or peptide/transporter conjugate formulation can be obtained by lyophilization of the following:
TABLE-US-00004 TABLE 3 Ingredient Amount (wt/vol) API 0.1 to 10.0 mg/mL Anti-aggregant Sugar 5.0 to 40.0 mg/mL WFI (USP) q.s. to 100
[0049] A preferred peptide or peptide/transporter conjugate formulation can be obtained by lyophilization of the following:
TABLE-US-00005 TABLE 4 Ingredient Amount (wt/vol) API 2.0 to 3.0 mg/mL Anti-aggregant Sugar 15.0 to 25.0 mg/mL WFI (USP) q.s. to 100
[0050] Another preferred peptide or peptide/transporter conjugate formulation can be obtained by lyophilization of the following:
TABLE-US-00006 TABLE 5 Ingredient Amount (wt/vol) API 0.5 to 5.0 mg/mL Anti-aggregant Sugar 10.0 to 30.0 mg/mL WFI (USP) q.s. to 100
[0051] Still another preferred peptide or peptide/transporter conjugate formulation can be obtained by lyophilization of the following:
TABLE-US-00007 TABLE 6 Ingredient Amount (wt/vol %) API 2.0 to 3.0 mg/mL Anti-aggregant Sugar 15.0 to 25.0 mg/mL WFI (USP) q.s. to 100
[0052] A further preferred peptide/transporter conjugate formulation can be obtained by lyophilization of the following:
TABLE-US-00008 TABLE 7 Ingredient Amount KAI-9803 5.0 mg Mannitol (USP) 40.0 mg WFI (USP) 2.0 mL
[0053] Alternatively, aqueous parenteral solutions of KAI-9803 can be prepared substantially free of sugars, at concentrations ranging from about 0.01 to about 10.0 mg/mL, preferably about 0.1 to about 5.0 mg/mL, and most preferably about 0.1 to about 1.0 mg/mL. The pH of such aqueous solutions is adjusted to between about 2.0 and 4.0, preferably between about 2.5 and 3.5.
Methods of Manufacture and Use
[0054] The PKC modulatory peptides and the transporter peptides can be synthesized according to conventional (e.g., solid phase) procedures. After activation of the Cys on one of the PKC modulatory and transporter peptides [e.g., using 2,2'-dithiobis(5-nitropyridine) to activate the carrier peptide] the two peptides are coupled, isolated and then purified [e.g., by preparative RP-HPLC using acetonitrile elution in a TEAP buffer (triethylamine and phosphoric acid) giving rise to the purified phosphate salt]. The fractions from the HPLC containing the purified and coupled peptides are then pooled. A pharmaceutically acceptable salt can be exchanged by repeat RP-HPLC eluting with acetonitrile and the desired organic or inorganic acid counter-ion donor (such as acetic acid, hydrochloric acid, tartaric acid and the like, preferably acetic acid). The desired end product is pooled, divided into lyophilization flasks, lyophilized, and transferred to suitable containers for storage prior to formulation (preferably in sealed amber glass containers at reduced temperature, e.g., -20° C.).
[0055] The counterion employed during the production of KAI-9803 has a positive effect on solubility and stability. An acetate counterion is used in the preferred embodiment. Other counterions, such as a chloride counterion are also contemplated. And while use of an acetate counterion is a preferred embodiment of the disclosed invention, it is not required.
[0056] The pharmaceutical formulations of the present invention can be manufactured according to most accepted practices, for example, as follows:
[0057] (A) Appropriate amounts of anti-aggregant, hydrophobic active agent and/or cationic transport moiety are introduced to a suitably sized container (preferably a glass vial) as dry solids.
[0058] (B) A pharmaceutically acceptable solvent [e.g., water for injection ("WFI")] is added to the container in an amount sufficient to dissolve the solids and attain a desired concentration.
[0059] (C) The solution thus-formed is filtered, aseptically dispensed into a pre-sterilized container, and lyophilized to dryness.
[0060] (D) The container is sealed (optionally after first filling the head-space with a non-reactive gas, such as nitrogen) for storage until reconstitution for administration.
[0061] It is recommended that such pharmaceutical products be stored at or below room temperature, preferably at about 2-8° C. (more preferably 5° C.), which instructions should be displayed on the container or its attached label, its outer packaging and any package insert included therein.
[0062] To reconstitute the lyophilized formulation for administration, the product is first warm to about room temperature before opening. Shortly prior to use, the sealed container is accessed via a needle through the rubber stopper and a pharmaceutically acceptable solvent (such as saline, preferably 9% saline) is added in an amount sufficient to solubilize the lyophilized cake and provide the desired concentration for administration. Such instructions for reconstitution can be provided in a pharmacy manual, on dosing cards, or can be incorporated on the container or its attached label, outer packaging and/or package insert.
Testing
[0063] Testing of the pharmaceutical formulations of the present invention can be accomplished by procedures well known in the art, for example, including: determination of active pharmaceutical ingredient identity and concentration by HPLC-UV (measuring absorbance at 206, 220 and/or 280 nm) e.g., before and after lyophilization and reconstitution; determination of water content in lyophilized product; pH of pre-lyophilized solution and reconstituted solution; and appearance of lyophilized cake.
EXAMPLES
[0064] The following examples serve to describe more fully the manner of using the above-described invention, as well as to set forth the best modes contemplated for carrying out various aspects of the invention. It is understood that these examples in no way serve to limit the true scope of this invention, but rather are presented for illustrative purposes. All references cited herein are incorporated by reference in their entirety.
Example 1
Manufacture of KAI-9803 Acetate
[0065] A. Peptide Fragment Synthesis
[0066] Merrifield resin is pre-swelled in dichloromethane (DCM) for at least 2 hours. The DCM is drained. Transporter and δ-PKC peptides are prepared by solid phase synthesis as follows:
[0067] 1. deprotection (TFA/DCM),
[0068] 2. resin washing (2-propanol, methanol, 10% TEA/DCM, methanol and DCM
[0069] 3. coupling of the next amino acid residue (t-Boc-AA-OH, using HOBt/HBTU/NMM), and
[0070] 4. resin washing (methanol and DCM)].
[0071] Deprotection and coupling are monitored by performance of a ninhydrin test. After incorporation of the final amino acid residue on each peptide (Cys), the resin peptide is deprotected and washed (steps 1, 2 and 4, above). The peptide-resin bond and side chain protecting groups are cleaved by treatment with HF/anisole and precipitated by ethyl ether.
[0072] B. Peptide Fragment Purification and Isolation
[0073] Transporter and d-PKC peptides obtained, e.g., as described in Example IA are subjected to preparative RP-HPLC on a C-18 column, using an acetonitrile gradient in trifluoroacetic acid solution. The acceptance criterion for purity of these intermediate peptides is not less than 90.0%.
[0074] C. Coupling
[0075] Transporter peptide obtained, e.g., as described in Example IB is activated by contact with 2,2'-dithiobis(5-nitropyridine) and then contacted with the δ-PKC peptide from Example IB to afford the coupled peptide conjugate KAI-9803.
[0076] D. Purification, Salt Exchange and Isolation
[0077] Crude KAI-9803 obtained, e.g., as described in Example IC is purified by preparative RP-HPLC using an acetonitrile elution in a TEAP buffer (triethylamine and phosphoric acid) on a YMC C-18 column. The fractions resulting from the purification are analyzed by an analytical RP-HPLC in-process method. Those fractions that meet the purity criterion (not less than 95%) are pooled, loaded back onto the same C-18 column and eluted with acetonitrile in an acetic acid buffer to give the corresponding KAI-9803 acetate salt. The thus-purified KAI-9803 acetate salt is pooled, divided into lyophilization flasks and frozen. The frozen flasks are connected to a lyophilizer manifold and the lyophilization is performed. Upon completion of lyophilization, the resulting KAI-9803 acetate powder is weighed, samples are taken for testing, and the remainder transferred into 50 mL amber glass containers. The containers are closed with 20 mm, (grey)butyl, snap-on stoppers, and stored at -20° C.
Example 2
Formulation, Lyophilization, Fill and Finish
[0078] KAI-9803 acetate powder (50.0 mg) obtained, e.g., as described in Example ID and mannitol USP (400.0 mg) are dissolved in about 14.0 mL of WFI, followed by the addition of WFI as necessary to total 20 ml (--6 ml) to give a clear, colorless solution. Clarity, color and complete dissolution of solids are confirmed by visual examination. The solution is aseptically filtered through two serial 0.22 μm filters into a class 100 aseptic filling suite. Two mL of the filtered solution are aseptically dispensed into each of ten pre-sterilized 20 mL vials. Each vial is capped with a slotted lyophilization stopper and loaded onto shelves pre-chilled to -50° C. A primary drying cycle is performed at a shelf temperature of 5° C. for not less than 20 hours, followed by a secondary drying step with a shelf temperature of 25° C. for not less than 3 hours. Upon completion of the lyophilization cycle, the vials are stoppered under nitrogen with a partial vacuum and sealed. The stoppered vials are crimped and inspected in a class 10,000 processing suite. The vials are labeled and then moved to 2-8° C. storage under quarantine.
Example 3
Reconstitution of a KAI-9803+Mannitol Formulation
[0079] A vial containing a lyophilized pharmaceutical formulation of 5 mg KAI-9803 and 40 mg mannitol (obtained, e.g., as described in Examples 1 and 2) is injected with 20 mL of 0.9% sodium chloride for injection, USP, is added to the vial and the contents are dissolved with gentle swirling to yield a clear solution. To a sterile, empty IV bag is added 18 mL of 0.9% sodium chloride for injection, USP, followed by the addition of 2 mL of KAI-9803 solution (taken from the vial) to yield a total volume of 20 mL of a 0.1 mg/mL solution of KAI-9803 in the IV bag. The solution is stored at room temperature and used within 4 hours of preparation.
Example 4
Stability of Lyophilized KAI-9803 Formulations
[0080] Formulations of KAI-9803 are prepared, for example as described in Examples 1 and 2, using mannitol and substituting mannitol with fructose and sucrose as the anti-aggregant sugar for the formulating procedure of Example 2. All of the solutions are visually inspected for clarity, color and complete dissolution of solids, and an aliquot is removed from each. Each aliquot is analyzed for KAI-9803 concentration using HPLC-UV, measuring absorbance at 206 and 280 nm. The remaining solutions are filtered, filled, lyophilized and finished, e.g., as described in Example 2. One set of vials representing each of the formulations is separated for immediate reconstitution and testing (HPLC-UV @206/280 nm) to confirm KAI-9803 concentration in the reconstituted product. The remaining vials are divided into groups for storage at reduced temperature (e.g., 2-8° C.), at room temperature, and at elevated temperature (e.g., 35° C.). Sets of vials representing each of the formulations are withdrawn at selected time points (e.g., 1 day, 1 week, 1 month, 3 months, 6 months), are reconstituted, visually inspected and tested for KAI-9803 concentration (HPLC-UV @206/280 nm).
[0081] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto. All patents and publications cited above are hereby incorporated by reference.
Sequence CWU
1
1
175123PRTArtificial SequencePKC modulatory peptide 1Cys Ser Phe Asn Ser
Tyr Glu Leu Gly Ser Leu Cys Tyr Gly Arg Lys1 5
10 15 Lys Arg Arg Gln Arg Arg Arg
20 28PRTArtificial SequencePKC modulatory peptide 2Ile Pro
Glu Gly Asp Glu Glu Gly1 5 36PRTArtificial
SequencePKC modulatory peptide 3Gln Leu Val Ile Ala Asn1 5
46PRTArtificial SequencePKC modulatory peptide 4Gly Leu Gly Ala Glu
Asn1 5 56PRTArtificial SequencePKC modulatory peptide
5Ala Arg Gly Ala Glu Asn1 5 67PRTArtificial
SequencePKC modulatory peptide 6Cys Gly Lys Gly Ala Glu Asn1
5 77PRTArtificial SequencePKC modulatory peptide 7Cys Gly Lys
Gly Ala Glu Asn1 5 88PRTArtificial SequencePKC
modulatory peptide 8Lys Gln Lys Thr Lys Thr Ile Lys1 5
913PRTArtificial SequencePKC modulatory peptide 9Met Asp Pro Asn
Gly Leu Ser Asp Pro Tyr Val Lys Leu1 5 10
107PRTArtificial SequencePKC modulatory peptide 10Ile Pro
Asp Pro Lys Ser Glu1 5 119PRTArtificial
SequencePKC modulatory peptide 11Ser Leu Asn Pro Glu Trp Asn Glu Thr1
5 128PRTArtificial SequencePKC modulatory
peptide 12Val Pro Pro Glu Gly Ser Glu Ala1 5
136PRTArtificial SequencePKC modulatory peptide 13Lys Leu Phe Ile Met
Asn1 5 147PRTArtificial SequencePKC modulatory peptide
14Arg Asp Lys Arg Asp Thr Ser1 5 159PRTArtificial
SequencePKC modulatory peptide 15Cys Ala Arg Asp Lys Arg Asp Thr Ser1
5 168PRTArtificial SequencePKC modulatory
peptide 16Gly Arg Asp Lys Arg Asp Thr Ser1 5
178PRTArtificial SequencePKC modulatory peptide 17Ala Arg Asp Lys Arg Asp
Thr Ser1 5 1812PRTArtificial SequencePKC
modulatory peptide 18Ala Arg Asp Lys Arg Asp Thr Ser Asn Phe Asp Lys1
5 10 1914PRTArtificial SequencePKC
modulatory peptide 19Ala Gly Phe Ser Tyr Thr Asn Pro Glu Phe Val Ile Asn
Val1 5 10
206PRTArtificial SequencePKC modulatory peptide 20Gln Glu Val Ile Arg
Asn1 5 216PRTArtificial SequencePKC modulatory peptide
21Cys Gly Arg Asn Ala Glu1 5 227PRTArtificial
SequencePKC modulatory peptide 22Ala Cys Gly Arg Asn Ala Glu1
5 237PRTArtificial SequencePKC modulatory peptide 23Ala Cys
Gly Lys Asn Ala Glu1 5 248PRTArtificial
SequencePKC modulatory peptide 24Lys Ala Cys Gly Arg Asn Ala Glu1
5 257PRTArtificial SequencePKC modulatory peptide
25Cys Gly Arg Asn Ala Glu Asn1 5 267PRTArtificial
SequencePKC modulatory peptide 26Ala Cys Gly Arg Asn Ala Glu1
5 2714PRTArtificial SequencePKC modulatory peptide 27Ser Phe
Val Asn Ser Glu Phe Leu Lys Pro Glu Val Leu Ser1 5
10 288PRTArtificial SequencePKC modulatory
peptide 28Val Ala Asp Ala Asp Asn Cys Ser1 5
296PRTArtificial SequencePKC modulatory peptide 29Gly Arg Ser Gly Glu
Asn1 5 306PRTArtificial SequencePKC modulatory peptide
30Gly Leu Ser Gly Glu Asn1 5 316PRTArtificial
SequencePKC modulatory peptide 31Arg Leu Val Leu Ala Ser1 5
328PRTArtificial SequencePKC modulatory peptide 32Pro Cys Gly Arg
Ser Gly Glu Asn1 5 3311PRTArtificial
SequencePKC modulatory peptide 33Cys Ser Phe Asn Ser Tyr Glu Leu Gly Ser
Leu1 5 10 3410PRTArtificial
SequencePKC modulatory peptide 34Ser Phe Asn Ser Tyr Glu Leu Gly Ser Leu1
5 10 3510PRTArtificial SequencePKC
modulatory peptide 35Thr Phe Asn Ser Tyr Glu Leu Gly Ser Leu1
5 10 3611PRTArtificial SequencePKC modulatory
peptide 36Ala Phe Asn Ser Asn Tyr Glu Leu Gly Ser Leu1 5
10 3710PRTArtificial SequencePKC modulatory peptide
37Ser Phe Asn Ser Tyr Glu Leu Gly Thr Leu1 5
10 3810PRTArtificial SequencePKC modulatory peptide 38Ser Thr Asn Ser
Tyr Glu Leu Gly Ser Leu1 5 10
3910PRTArtificial SequencePKC modulatory peptide 39Ser Phe Asn Ser Phe
Glu Leu Gly Ser Leu1 5 10
409PRTArtificial SequencePKC modulatory peptide 40Ser Asn Ser Tyr Asp Leu
Gly Ser Leu1 5 4110PRTArtificial
SequencePKC modulatory peptide 41Ser Phe Asn Ser Tyr Glu Leu Pro Ser Leu1
5 10 4210PRTArtificial SequencePKC
modulatory peptide 42Thr Phe Asn Ser Tyr Glu Leu Gly Thr Leu1
5 10 4310PRTArtificial SequencePKC modulatory
peptide 43Ser Phe Asn Ser Tyr Glu Ile Gly Ser Val1 5
10 4410PRTArtificial SequencePKC modulatory peptide 44Ser Phe
Asn Ser Tyr Glu Val Gly Ser Ile1 5 10
4510PRTArtificial SequencePKC modulatory peptide 45Ser Phe Asn Ser Tyr
Glu Leu Gly Ser Val1 5 10
4610PRTArtificial SequencePKC modulatory peptide 46Ser Phe Asn Ser Tyr
Glu Leu Gly Ser Ile1 5 10
4710PRTArtificial SequencePKC modulatory peptide 47Ser Phe Asn Ser Tyr
Glu Ile Gly Ser Leu1 5 10
4810PRTArtificial SequencePKC modulatory peptide 48Ser Phe Asn Ser Tyr
Glu Val Gly Ser Leu1 5 10
4910PRTArtificial SequencePKC modulatory peptide 49Ala Phe Asn Ser Tyr
Glu Leu Gly Ser Leu1 5 10
506PRTArtificial SequencePKC modulatory peptide 50Tyr Asp Leu Gly Ser
Leu1 5 516PRTArtificial SequencePKC modulatory peptide
51Phe Asp Leu Gly Ser Leu1 5 526PRTArtificial
SequencePKC modulatory peptide 52Tyr Asp Ile Gly Ser Leu1 5
536PRTArtificial SequencePKC modulatory peptide 53Tyr Asp Val Gly
Ser Leu1 5 546PRTArtificial SequencePKC modulatory
peptide 54Tyr Asp Leu Pro Ser Leu1 5 556PRTArtificial
SequencePKC modulatory peptide 55Tyr Asp Leu Gly Leu Leu1 5
566PRTArtificial SequencePKC modulatory peptide 56Tyr Asp Leu Gly
Ser Ile1 5 576PRTArtificial SequencePKC modulatory
peptide 57Tyr Asp Leu Gly Ser Val1 5 584PRTArtificial
SequencePKC modulatory peptide 58Ile Gly Ser Leu1
594PRTArtificial SequencePKC modulatory peptide 59Val Gly Ser Leu1
604PRTArtificial SequencePKC modulatory peptide 60Leu Pro Ser Leu1
614PRTArtificial SequencePKC modulatory peptide 61Leu Gly Leu
Leu1 624PRTArtificial SequencePKC modulatory peptide 62Leu
Gly Ser Ile1 634PRTArtificial SequencePKC modulatory peptide
63Leu Gly Ser Val1 6411PRTArtificial SequencePKC modulatory
peptide 64Ala Leu Ser Thr Glu Arg Gly Lys Thr Leu Val1 5
10 6511PRTArtificial SequencePKC modulatory peptide
65Ala Leu Ser Thr Asp Arg Gly Lys Thr Leu Val1 5
10 6611PRTArtificial SequencePKC modulatory peptide 66Ala Leu
Thr Ser Asp Arg Gly Lys Thr Leu Val1 5 10
6711PRTArtificial SequencePKC modulatory peptide 67Ala Leu Thr Thr
Asp Arg Gly Lys Ser Leu Val1 5 10
6811PRTArtificial SequencePKC modulatory peptide 68Ala Leu Thr Thr Asp
Arg Pro Lys Thr Leu Val1 5 10
6911PRTArtificial SequencePKC modulatory peptide 69Ala Leu Thr Thr Asp
Arg Gly Arg Thr Leu Val1 5 10
7011PRTArtificial SequencePKC modulatory peptide 70Ala Leu Thr Thr Asp
Lys Gly Lys Thr Leu Val1 5 10
7111PRTArtificial SequencePKC modulatory peptide 71Ala Leu Thr Thr Asp
Lys Gly Lys Thr Leu Val1 5 10
7210PRTArtificial SequencePKC modulatory peptide 72Val Leu Met Arg Ala
Ala Glu Glu Pro Val1 5 10
7310PRTArtificial SequencePKC modulatory peptide 73Gln Ser Met Arg Ser
Glu Asp Glu Ala Lys1 5 10
749PRTArtificial SequencePKC modulatory peptide 74Gln Gly Phe Glu Lys Lys
Thr Gly Val1 5 759PRTArtificial
SequencePKC modulatory peptide 75Asp Asn Asn Gly Thr Tyr Gly Lys Ile1
5 766PRTArtificial SequencePKC modulatory
peptide 76Lys Asn Leu Ile Asp Ser1 5 778PRTArtificial
SequencePKC modulatory peptide 77Val Lys Ser Pro Arg Asp Tyr Ser1
5 789PRTArtificial SequencePKC modulatory peptide
78Val Lys Ser Pro Cys Arg Asp Tyr Ser1 5
798PRTArtificial SequencePKC modulatory peptide 79Ile Lys Ser Pro Arg Leu
Tyr Ser1 5 806PRTArtificial SequencePKC
modulatory peptide 80Lys Asn Leu Ile Asp Ser1 5
8111PRTArtificial SequencePKC modulatory peptide 81Pro Lys Val Lys Ser
Pro Arg Asp Tyr Ser Asn1 5 10
827PRTArtificial SequencePKC modulatory peptide 82Asn Gly Leu Leu Lys Ile
Lys1 5 838PRTArtificial SequencePKC modulatory
peptide 83Glu Ala Val Ser Leu Lys Pro Thr1 5
8411PRTArtificial SequencePKC modulatory peptide 84Leu Ala Val Phe His
Asp Ala Pro Ile Gly Tyr1 5 10
859PRTArtificial SequencePKC modulatory peptide 85Asp Asp Phe Val Ala Asn
Cys Thr Ile1 5 8610PRTArtificial
SequencePKC modulatory peptide 86Trp Ile Asp Leu Glu Pro Glu Gly Arg Val1
5 10 8710PRTArtificial SequencePKC
modulatory peptide 87His Ala Val Gly Pro Arg Pro Gln Thr Phe1
5 10 888PRTArtificial SequencePKC modulatory peptide
88Asn Gly Ser Arg His Phe Glu Asp1 5
898PRTArtificial SequencePKC modulatory peptide 89His Asp Ala Pro Ile Gly
Asp Tyr1 5 906PRTArtificial SequencePKC
modulatory peptide 90His Asp Ala Pro Ile Gly1 5
918PRTArtificial SequencePKC modulatory peptide 91His Asp Ala Ala Ile Gly
Tyr Asp1 5 928PRTArtificial SequencePKC
modulatory peptide 92His Asp Ala Pro Ile Pro Tyr Asp1 5
938PRTArtificial SequencePKC modulatory peptide 93His Asn Ala
Pro Ile Gly Tyr Asp1 5 948PRTArtificial
SequencePKC modulatory peptide 94His Ala Ala Pro Ile Gly Tyr Asp1
5 958PRTArtificial SequencePKC modulatory peptide
95Ala Asp Ala Pro Ile Gly Tyr Asp1 5
968PRTArtificial SequencePKC modulatory peptide 96His Asp Ala Pro Ala Gly
Tyr Asp1 5 978PRTArtificial SequencePKC
modulatory peptide 97His Asp Ala Pro Ile Gly Ala Asp1 5
988PRTArtificial SequencePKC modulatory peptide 98His Asp Ala
Pro Ile Ala Tyr Asp1 5 998PRTArtificial
SequencePKC modulatory peptide 99His Asp Ala Pro Ile Gly Tyr Ala1
5 1009PRTArtificial SequencePKC modulatory peptide
100Ser Ser Pro Ser Glu Glu Asp Arg Ser1 5
1018PRTArtificial SequencePKC modulatory peptide 101Pro Cys Asp Gln Glu
Ile Lys Glu1 5 1029PRTArtificial SequencePKC
modulatory peptide 102Glu Asn Asn Ile Arg Lys Ala Leu Ser1
5 1038PRTArtificial SequencePKC modulatory peptide
103Gly Glu Val Arg Gln Gly Gln Ala1 5
1046PRTArtificial SequencePKC modulatory peptide 104Glu Ala Ile Val Lys
Gln1 5 1057PRTArtificial SequencePKC modulatory
peptide 105Ile Lys Thr Lys Arg Asp Val1 5
1067PRTArtificial SequencePKC modulatory peptide 106Ile Lys Thr Lys Arg
Leu Ile1 5 1077PRTArtificial SequencePKC
modulatory peptide 107Cys Glu Ala Ile Val Lys Gln1 5
10810PRTArtificial SequencePKC modulatory peptide 108Thr Lys Arg Asp
Val Asn Asn Phe Asp Gln1 5 10
1097PRTArtificial SequencePKC modulatory peptide 109Val Arg Leu Lys Ala
His Tyr1 5 1106PRTArtificial SequencePKC
modulatory peptide 110Val Asp Ser Glu Gly Asp1 5
1118PRTArtificial SequencePKC modulatory peptide 111Val Phe Pro Ser Ile
Pro Glu Gln1 5 11215PRTArtificial SequencePKC
modulatory peptide 112Ser Gln Glu Pro Pro Val Asp Asp Lys Asn Glu Asp Ala
Asp Leu1 5 10 15
1137PRTArtificial SequencePKC modulatory peptide 113Ile Lys Asp Asp Ser
Glu Asp1 5 1149PRTArtificial SequencePKC
modulatory peptide 114Pro Val Ile Asp Gly Met Asp Gly Ile1
5 1156PRTArtificial SequencePKC modulatory peptide
115Glu Asp Ala Ile Lys Arg1 5 1165PRTArtificial
SequencePKC modulatory peptide 116Glu Asp Ala Ile Arg1 5
1178PRTArtificial SequencePKC modulatory peptide 117Ile Thr Asp Asp Tyr
Gly Leu Asp1 5 1188PRTArtificial SequencePKC
modulatory peptide 118Ile Thr Asp Asp Tyr Gly Asp Leu1 5
1197PRTArtificial SequencePKC modulatory peptide 119Asp Asp Tyr
Gly Leu Asp Asn1 5 1207PRTArtificial SequencePKC
modulatory peptide 120Asn Gly Tyr Leu Arg Val Arg1 5
1218PRTArtificial SequencePKC modulatory peptide 121Glu Ala Val Gly Leu
Gln Pro Thr1 5 12211PRTArtificial SequencePKC
modulatory peptide 122Leu Ala Val Phe His Glu Thr Pro Leu Gly Tyr1
5 10 1238PRTArtificial SequencePKC
modulatory peptide 123Asp Phe Val Ala Asn Cys Thr Leu1 5
12410PRTArtificial SequencePKC modulatory peptide 124Trp Val
Asp Leu Glu Pro Glu Gly Lys Val1 5 10
1258PRTArtificial SequencePKC modulatory peptide 125His Ser Leu Phe Lys
Lys Gly His1 5 1269PRTArtificial SequencePKC
modulatory peptide 126Thr Gly Ala Ser Asp Thr Phe Glu Gly1
5 1276PRTArtificial SequencePKC modulatory peptide
127Glu Gly His Leu Pro Met1 5 1286PRTArtificial
SequencePKC modulatory peptide 128Glu Gly His Asp Pro Met1
5 1298PRTArtificial SequencePKC modulatory peptide 129Ile Lys Ser
Arg Glu Asp Val Ser1 5 1308PRTArtificial
SequencePKC modulatory peptide 130Val Arg Ser Arg Glu Asp Val Ser1
5 1319PRTArtificial SequencePKC modulatory peptide
131Pro Arg Ile Lys Ser Arg Glu Asp Val1 5
13210PRTArtificial SequencePKC modulatory peptide 132His Gln Val Arg Val
Lys Ala Tyr Tyr Arg1 5 10
13311PRTArtificial SequencePKC modulatory peptide 133Tyr Glu Leu Asn Lys
Asp Ser Glu Leu Leu Ile1 5 10
13415PRTArtificial SequencePKC modulatory peptide 134Met Asp Gln Ser Ser
Met His Ser Asp His Ala Gln Thr Val Ile1 5
10 15 1357PRTArtificial SequencePKC modulatory peptide
135Leu Asp Gln Val Gly Glu Glu1 5
1369PRTArtificial SequencePKC modulatory peptide 136Glu Ala Met Asn Thr
Arg Glu Ser Gly1 5 1376PRTArtificial
SequencePKC modulatory peptide 137Asp Asp Ile Val Arg Lys1
5 1388PRTArtificial SequencePKC modulatory peptide 138Val Lys Leu
Cys Asp Phe Gly Phe1 5 1398PRTArtificial
SequencePKC modulatory peptide 139Ile Arg Leu Cys Asp Phe Ala Phe1
5 14010PRTArtificial SequencePKC modulatory peptide
140Gln Val Lys Leu Cys Asp Phe Gly Phe Ala1 5
10 1419PRTArtificial SequencePKC modulatory peptide 141Met Ser Val
Pro Pro Leu Leu Arg Pro1 5
14211PRTArtificial SequencePKC modulatory peptide 142Lys Phe Pro Glu Cys
Gly Phe Tyr Gly Leu Tyr1 5 10
1439PRTArtificial SequencePKC modulatory peptide 143Asp Pro Asp Ala Asp
Gln Glu Asp Ser1 5 1449PRTArtificial
SequencePKC modulatory peptide 144Ser Lys Asp Thr Leu Arg Lys Arg His1
5 1459PRTArtificial SequencePKC modulatory
peptide 145Ile Thr Leu Phe Gln Asn Asp Thr Gly1 5
1469PRTArtificial SequencePKC modulatory peptide 146Gly Ser Asn
Ser His Lys Asp Ile Ser1 5
1476PRTArtificial SequencePKC modulatory peptide 147Ser Asp Ser Pro Glu
Ala1 5 1488PRTArtificial SequencePKC modulatory
peptide 148Gly Leu Ser Asn Phe Asp Cys Gly1 5
14911PRTArtificial SequencePKC modulatory peptide 149Tyr Val Glu Ser Glu
Asn Gly Gln Met Tyr Ile1 5 10
15010PRTArtificial SequencePKC modulatory peptide 150Ile Val Lys Gly Lys
Asn Val Asp Leu Ile1 5 10
15110PRTArtificial SequencePKC modulatory peptide 151Asp Met Asn Glu Phe
Glu Thr Glu Gly Phe1 5 10
1529PRTArtificial SequencePKC modulatory peptide 152Cys Ser Ile Lys Asn
Glu Ala Arg Leu1 5 1539PRTArtificial
SequencePKC modulatory peptide 153Gly Lys Arg Glu Pro Gln Gly Ile Ser1
5 1549PRTArtificial SequencePKC modulatory
peptide 154Asp Glu Val Asp Lys Met Cys His Leu1 5
1556PRTArtificial SequencePKC modulatory peptide 155Arg Ala Leu
Ile Asn Ser1 5 1568PRTArtificial SequencePKC
modulatory peptide 156Val Lys Ser Pro Phe Asp Cys Ser1 5
1578PRTArtificial SequencePKC modulatory peptide 157Val Arg Ser
Pro Phe Asp Cys Ser1 5 1587PRTArtificial
SequencePKC modulatory peptide 158Asp Arg Ala Leu Ile Asn Ser1
5 1598PRTArtificial SequencePKC modulatory peptide 159Ile Ser
Gly Glu Phe Gly Leu Asp1 5 1608PRTArtificial
SequencePKC modulatory peptide 160Cys Ser Gly Glu Phe Gly Leu Asp1
5 1617PRTArtificial SequencePKC modulatory peptide
161Asp Asp Asp Ile Val Arg Lys1 5
1626PRTArtificial SequencePKC modulatory peptide 162Asp Asp Ile Val Arg
Lys1 5 1639PRTArtificial SequencePKC modulatory
peptide 163Ala Phe Asn Ser Tyr Glu Leu Gly Ser1 5
164672PRTHomo sapiens 164Met Ala Asp Val Phe Pro Gly Asn Asp Ser
Thr Ala Ser Gln Asp Val1 5 10
15 Ala Asn Arg Phe Ala Arg Lys Gly Ala Leu Arg Gln Lys Asn Val
His 20 25 30 Glu
Val Lys Asp His Lys Phe Ile Ala Arg Phe Phe Lys Gln Pro Thr 35
40 45 Phe Cys Ser His Cys Thr
Asp Phe Ile Trp Gly Phe Gly Lys Gln Gly 50 55
60 Phe Gln Cys Gln Val Cys Cys Phe Val Val His
Lys Arg Cys His Glu65 70 75
80 Phe Val Thr Phe Ser Cys Pro Gly Ala Asp Lys Gly Pro Asp Thr Asp
85 90 95 Asp Pro Arg
Ser Lys His Lys Phe Lys Ile His Thr Tyr Gly Ser Pro 100
105 110 Thr Phe Cys Asp His Cys Gly Ser
Leu Leu Tyr Gly Leu Ile His Gln 115 120
125 Gly Met Lys Cys Asp Thr Cys Asp Met Asn Val His Lys
Gln Cys Val 130 135 140
Ile Asn Val Pro Ser Leu Cys Gly Met Asp His Thr Glu Lys Arg Gly145
150 155 160 Arg Ile Tyr Leu Lys
Ala Glu Val Ala Asp Glu Lys Leu His Val Thr 165
170 175 Val Arg Asp Ala Lys Asn Leu Ile Pro Met
Asp Pro Asn Gly Leu Ser 180 185
190 Asp Pro Tyr Val Lys Leu Lys Leu Ile Pro Asp Pro Lys Asn Glu
Ser 195 200 205 Lys
Gln Lys Thr Lys Thr Ile Arg Ser Thr Leu Asn Pro Gln Trp Asn 210
215 220 Glu Ser Phe Thr Phe Lys
Leu Lys Pro Ser Asp Lys Asp Arg Arg Leu225 230
235 240 Ser Val Glu Ile Trp Asp Trp Asp Arg Thr Thr
Arg Asn Asp Phe Met 245 250
255 Gly Ser Leu Ser Phe Gly Val Ser Glu Leu Met Lys Met Pro Ala Ser
260 265 270 Gly Trp Tyr
Lys Leu Leu Asn Gln Glu Glu Gly Glu Tyr Tyr Asn Val 275
280 285 Pro Ile Pro Glu Gly Asp Glu Glu
Gly Asn Met Glu Leu Arg Gln Lys 290 295
300 Phe Glu Lys Ala Lys Leu Gly Pro Ala Gly Asn Lys Val
Ile Ser Pro305 310 315
320 Ser Glu Asp Arg Lys Gln Pro Ser Asn Asn Leu Asp Arg Val Lys Leu
325 330 335 Thr Asp Phe Asn
Phe Leu Met Val Leu Gly Lys Gly Ser Phe Gly Lys 340
345 350 Val Met Leu Ala Asp Arg Lys Gly Thr
Glu Glu Leu Tyr Ala Ile Lys 355 360
365 Ile Leu Lys Lys Asp Val Val Ile Gln Asp Asp Asp Val Glu
Cys Thr 370 375 380
Met Val Glu Lys Arg Val Leu Ala Leu Leu Asp Lys Pro Pro Phe Leu385
390 395 400 Thr Gln Leu His Ser
Cys Phe Gln Thr Val Asp Arg Leu Tyr Phe Val 405
410 415 Met Glu Tyr Val Asn Gly Gly Asp Leu Met
Tyr His Ile Gln Gln Val 420 425
430 Gly Lys Phe Lys Glu Pro Gln Ala Val Phe Tyr Ala Ala Glu Ile
Ser 435 440 445 Ile
Gly Leu Phe Phe Leu His Lys Arg Gly Ile Ile Tyr Arg Asp Leu 450
455 460 Lys Leu Asp Asn Val Met
Leu Asp Ser Glu Gly His Ile Lys Ile Ala465 470
475 480 Asp Phe Gly Met Cys Lys Glu His Met Met Asp
Gly Val Thr Thr Arg 485 490
495 Thr Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile Ile Ala Tyr
500 505 510 Gln Pro Tyr
Gly Lys Ser Val Asp Trp Trp Ala Tyr Gly Val Leu Leu 515
520 525 Tyr Glu Met Leu Ala Gly Gln Pro
Pro Phe Asp Gly Glu Asp Glu Asp 530 535
540 Glu Leu Phe Gln Ser Ile Met Glu His Asn Val Ser Tyr
Pro Lys Ser545 550 555
560 Leu Ser Lys Glu Ala Val Ser Ile Cys Lys Gly Leu Met Thr Lys His
565 570 575 Pro Ala Lys Arg
Leu Gly Cys Gly Pro Glu Gly Glu Arg Asp Val Arg 580
585 590 Glu His Ala Phe Phe Arg Arg Ile Asp
Trp Glu Lys Leu Glu Asn Arg 595 600
605 Glu Ile Gln Pro Pro Phe Lys Pro Lys Val Cys Gly Lys Gly
Ala Glu 610 615 620
Asn Phe Asp Lys Phe Phe Thr Arg Gly Gln Pro Val Leu Thr Pro Pro625
630 635 640 Asp Gln Leu Val Ile
Ala Asn Ile Asp Gln Ser Asp Phe Glu Gly Phe 645
650 655 Ser Tyr Val Asn Pro Gln Phe Val His Pro
Ile Leu Gln Ser Ala Val 660 665
670 165671PRTHomo sapiens 165Met Ala Asp Pro Ala Ala Gly Pro Pro
Pro Ser Glu Gly Glu Glu Ser1 5 10
15 Thr Val Arg Phe Ala Arg Lys Gly Ala Leu Arg Gln Lys Asn
Val His 20 25 30
Glu Val Lys Asn His Lys Phe Thr Ala Arg Phe Phe Lys Gln Pro Thr 35
40 45 Phe Cys Ser His Cys
Thr Asp Phe Ile Trp Gly Phe Gly Lys Gln Gly 50 55
60 Phe Gln Cys Gln Val Cys Cys Phe Val Val
His Lys Arg Cys His Glu65 70 75
80 Phe Val Thr Phe Ser Cys Pro Gly Ala Asp Lys Gly Pro Ala Ser
Asp 85 90 95 Asp
Pro Arg Ser Lys His Lys Phe Lys Ile His Thr Tyr Ser Ser Pro
100 105 110 Thr Phe Cys Asp His
Cys Gly Ser Leu Leu Tyr Gly Leu Ile His Gln 115
120 125 Gly Met Lys Cys Asp Thr Cys Met Met
Asn Val His Lys Arg Cys Val 130 135
140 Met Asn Val Pro Ser Leu Cys Gly Thr Asp His Thr Glu
Arg Arg Gly145 150 155
160 Arg Ile Tyr Ile Gln Ala His Ile Asp Arg Asp Val Leu Ile Val Leu
165 170 175 Val Arg Asp Ala
Lys Asn Leu Val Pro Met Asp Pro Asn Gly Leu Ser 180
185 190 Asp Pro Tyr Val Lys Leu Lys Leu Ile
Pro Asp Pro Lys Ser Glu Ser 195 200
205 Lys Gln Lys Thr Lys Thr Ile Lys Cys Ser Leu Asn Pro Glu
Trp Asn 210 215 220
Glu Thr Phe Arg Phe Gln Leu Lys Glu Ser Asp Lys Asp Arg Arg Leu225
230 235 240 Ser Val Glu Ile Trp
Asp Trp Asp Leu Thr Ser Arg Asn Asp Phe Met 245
250 255 Gly Ser Leu Ser Phe Gly Ile Ser Glu Leu
Gln Lys Ala Ser Val Asp 260 265
270 Gly Trp Phe Lys Leu Leu Ser Gln Glu Glu Gly Glu Tyr Phe Asn
Val 275 280 285 Pro
Val Pro Pro Glu Gly Ser Glu Ala Asn Glu Glu Leu Arg Gln Lys 290
295 300 Phe Glu Arg Ala Lys Ile
Ser Gln Gly Thr Lys Val Pro Glu Glu Lys305 310
315 320 Thr Thr Asn Thr Val Ser Lys Phe Asp Asn Asn
Gly Asn Arg Asp Arg 325 330
335 Met Lys Leu Thr Asp Phe Asn Phe Leu Met Val Leu Gly Lys Gly Ser
340 345 350 Phe Gly Lys
Val Met Leu Ser Glu Arg Lys Gly Thr Asp Glu Leu Tyr 355
360 365 Ala Val Lys Ile Leu Lys Lys Asp
Val Val Ile Gln Asp Asp Asp Val 370 375
380 Glu Cys Thr Met Val Glu Lys Arg Val Leu Ala Leu Pro
Gly Lys Pro385 390 395
400 Pro Phe Leu Thr Gln Leu His Ser Cys Phe Gln Thr Met Asp Arg Leu
405 410 415 Tyr Phe Val Met
Glu Tyr Val Asn Gly Gly Asp Leu Met Tyr His Ile 420
425 430 Gln Gln Val Gly Arg Phe Lys Glu Pro
His Ala Val Phe Tyr Ala Ala 435 440
445 Glu Ile Ala Ile Gly Leu Phe Phe Leu Gln Ser Lys Gly Ile
Ile Tyr 450 455 460
Arg Asp Leu Lys Leu Asp Asn Val Met Leu Asp Ser Glu Gly His Ile465
470 475 480 Lys Ile Ala Asp Phe
Gly Met Cys Lys Glu Asn Ile Trp Asp Gly Val 485
490 495 Thr Thr Lys Thr Phe Cys Gly Thr Pro Asp
Tyr Ile Ala Pro Glu Ile 500 505
510 Ile Ala Tyr Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ala Phe
Gly 515 520 525 Val
Leu Leu Tyr Glu Met Leu Ala Gly Gln Ala Pro Phe Glu Gly Glu 530
535 540 Asp Glu Asp Glu Leu Phe
Gln Ser Ile Met Glu His Asn Val Ala Tyr545 550
555 560 Pro Lys Ser Met Ser Lys Glu Ala Val Ala Ile
Cys Lys Gly Leu Met 565 570
575 Thr Lys His Pro Gly Lys Arg Leu Gly Cys Gly Pro Glu Gly Glu Arg
580 585 590 Asp Ile Lys
Glu His Ala Phe Phe Arg Tyr Ile Asp Trp Glu Lys Leu 595
600 605 Glu Arg Lys Glu Ile Gln Pro Pro
Tyr Lys Pro Lys Ala Arg Asp Lys 610 615
620 Arg Asp Thr Ser Asn Phe Asp Lys Glu Phe Thr Arg Gln
Pro Val Glu625 630 635
640 Leu Thr Pro Thr Asp Lys Leu Phe Ile Met Asn Leu Asp Gln Asn Glu
645 650 655 Phe Ala Gly Phe
Ser Tyr Thr Asn Pro Glu Phe Val Ile Asn Val 660
665 670 166673PRTHomo sapiens 166Met Ala Asp Pro Ala
Ala Gly Pro Pro Pro Ser Glu Gly Glu Glu Ser1 5
10 15 Thr Val Arg Phe Ala Arg Lys Gly Ala Leu
Arg Gln Lys Asn Val His 20 25
30 Glu Val Lys Asn His Lys Phe Thr Ala Arg Phe Phe Lys Gln Pro
Thr 35 40 45 Phe
Cys Ser His Cys Thr Asp Phe Ile Trp Gly Phe Gly Lys Gln Gly 50
55 60 Phe Gln Cys Gln Val Cys
Cys Phe Val Val His Lys Arg Cys His Glu65 70
75 80 Phe Val Thr Phe Ser Cys Pro Gly Ala Asp Lys
Gly Pro Ala Ser Asp 85 90
95 Asp Pro Arg Ser Lys His Lys Phe Lys Ile His Thr Tyr Ser Ser Pro
100 105 110 Thr Phe Cys
Asp His Cys Gly Ser Leu Leu Tyr Gly Leu Ile His Gln 115
120 125 Gly Met Lys Cys Asp Thr Cys Met
Met Asn Val His Lys Arg Cys Val 130 135
140 Met Asn Val Pro Ser Leu Cys Gly Thr Asp His Thr Glu
Arg Arg Gly145 150 155
160 Arg Ile Tyr Ile Gln Ala His Ile Asp Arg Asp Val Leu Ile Val Leu
165 170 175 Val Arg Asp Ala
Lys Asn Leu Val Pro Met Asp Pro Asn Gly Leu Ser 180
185 190 Asp Pro Tyr Val Lys Leu Lys Leu Ile
Pro Asp Pro Lys Ser Glu Ser 195 200
205 Lys Gln Lys Thr Lys Thr Ile Lys Cys Ser Leu Asn Pro Glu
Trp Asn 210 215 220
Glu Thr Phe Arg Phe Gln Leu Lys Glu Ser Asp Lys Asp Arg Arg Leu225
230 235 240 Ser Val Glu Ile Trp
Asp Trp Asp Leu Thr Ser Arg Asn Asp Phe Met 245
250 255 Gly Ser Leu Ser Phe Gly Ile Ser Glu Leu
Gln Lys Ala Ser Val Asp 260 265
270 Gly Trp Phe Lys Leu Leu Ser Gln Glu Glu Gly Glu Tyr Phe Asn
Val 275 280 285 Pro
Val Pro Pro Glu Gly Ser Glu Ala Asn Glu Glu Leu Arg Gln Lys 290
295 300 Phe Glu Arg Ala Lys Ile
Ser Gln Gly Thr Lys Val Pro Glu Glu Lys305 310
315 320 Thr Thr Asn Thr Val Ser Lys Phe Asp Asn Asn
Gly Asn Arg Asp Arg 325 330
335 Met Lys Leu Thr Asp Phe Asn Phe Leu Met Val Leu Gly Lys Gly Ser
340 345 350 Phe Gly Lys
Val Met Leu Ser Glu Arg Lys Gly Thr Asp Glu Leu Tyr 355
360 365 Ala Val Lys Ile Leu Lys Lys Asp
Val Val Ile Gln Asp Asp Asp Val 370 375
380 Glu Cys Thr Met Val Glu Lys Arg Val Leu Ala Leu Pro
Gly Lys Pro385 390 395
400 Pro Phe Leu Thr Gln Leu His Ser Cys Phe Gln Thr Met Asp Arg Leu
405 410 415 Tyr Phe Val Met
Glu Tyr Val Asn Gly Gly Asp Leu Met Tyr His Ile 420
425 430 Gln Gln Val Gly Arg Phe Lys Glu Pro
His Ala Val Phe Tyr Ala Ala 435 440
445 Glu Ile Ala Ile Gly Leu Phe Phe Leu Gln Ser Lys Gly Ile
Ile Tyr 450 455 460
Arg Asp Leu Lys Leu Asp Asn Val Met Leu Asp Ser Glu Gly His Ile465
470 475 480 Lys Ile Ala Asp Phe
Gly Met Cys Lys Glu Asn Ile Trp Asp Gly Val 485
490 495 Thr Thr Lys Thr Phe Cys Gly Thr Pro Asp
Tyr Ile Ala Pro Glu Ile 500 505
510 Ile Ala Tyr Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ala Phe
Gly 515 520 525 Val
Leu Leu Tyr Glu Met Leu Ala Gly Gln Ala Pro Phe Glu Gly Glu 530
535 540 Asp Glu Asp Glu Leu Phe
Gln Ser Ile Met Glu His Asn Val Ala Tyr545 550
555 560 Pro Lys Ser Met Ser Lys Glu Ala Val Ala Ile
Cys Lys Gly Leu Met 565 570
575 Thr Lys His Pro Gly Lys Arg Leu Gly Cys Gly Pro Glu Gly Glu Arg
580 585 590 Asp Ile Lys
Glu His Ala Phe Phe Arg Tyr Ile Asp Trp Glu Lys Leu 595
600 605 Glu Arg Lys Glu Ile Gln Pro Pro
Tyr Lys Pro Lys Ala Cys Gly Arg 610 615
620 Asn Ala Glu Asn Phe Asp Arg Phe Phe Thr Arg His Pro
Pro Val Leu625 630 635
640 Thr Pro Pro Asp Gln Glu Val Ile Arg Asn Ile Asp Gln Ser Glu Phe
645 650 655 Glu Gly Phe Ser
Phe Val Asn Ser Glu Phe Leu Lys Pro Glu Val Lys 660
665 670 Ser167697PRTHomo sapiens 167Met Ala
Gly Leu Gly Pro Gly Val Gly Asp Ser Glu Gly Gly Pro Arg1 5
10 15 Pro Leu Phe Cys Arg Lys Gly
Ala Leu Arg Gln Lys Val Val His Glu 20 25
30 Val Lys Ser His Lys Phe Thr Ala Arg Phe Phe Lys
Gln Pro Thr Phe 35 40 45
Cys Ser His Cys Thr Asp Phe Ile Trp Gly Ile Gly Lys Gln Gly Leu
50 55 60 Gln Cys Gln
Val Cys Ser Phe Val Val His Arg Arg Cys His Glu Phe65 70
75 80 Val Thr Phe Glu Cys Pro Gly Ala
Gly Lys Gly Pro Gln Thr Asp Asp 85 90
95 Pro Arg Asn Lys His Lys Phe Arg Leu His Ser Tyr Ser
Ser Pro Thr 100 105 110
Phe Cys Asp His Cys Gly Ser Leu Leu Tyr Gly Leu Val His Gln Gly
115 120 125 Met Lys Cys Ser
Cys Cys Glu Met Asn Val His Arg Arg Cys Val Arg 130
135 140 Ser Val Pro Ser Leu Cys Gly Val
Asp His Thr Glu Arg Arg Gly Arg145 150
155 160 Leu Gln Leu Glu Ile Arg Ala Pro Thr Ala Asp Glu
Ile His Val Thr 165 170
175 Val Gly Glu Ala Arg Asn Leu Ile Pro Met Asp Pro Asn Gly Leu Ser
180 185 190 Asp Pro Tyr
Val Lys Leu Lys Leu Ile Pro Asp Pro Arg Asn Leu Thr 195
200 205 Lys Gln Lys Thr Arg Thr Val Lys
Ala Thr Leu Asn Pro Val Trp Asn 210 215
220 Glu Thr Phe Val Phe Asn Leu Lys Pro Gly Asp Val Glu
Arg Arg Leu225 230 235
240 Ser Val Glu Val Trp Asp Trp Asp Arg Thr Ser Arg Asn Asp Phe Met
245 250 255 Gly Ala Met Ser
Phe Gly Val Ser Glu Leu Leu Lys Ala Pro Val Asp 260
265 270 Gly Trp Tyr Lys Leu Leu Asn Gln Glu
Glu Gly Glu Tyr Tyr Asn Val 275 280
285 Pro Val Ala Asp Ala Asp Asn Cys Ser Leu Leu Gln Lys Phe
Glu Ala 290 295 300
Cys Asn Tyr Pro Leu Glu Leu Tyr Glu Arg Val Arg Met Gly Pro Ser305
310 315 320 Ser Ser Pro Ile Pro
Ser Pro Ser Pro Ser Pro Thr Asp Pro Lys Arg 325
330 335 Cys Phe Phe Gly Ala Ser Pro Gly Arg Leu
His Ile Ser Asp Phe Ser 340 345
350 Phe Leu Met Val Leu Gly Lys Gly Ser Phe Gly Lys Val Met Leu
Ala 355 360 365 Glu
Arg Arg Gly Ser Asp Glu Leu Tyr Ala Ile Lys Ile Leu Lys Lys 370
375 380 Asp Val Ile Val Gln Asp
Asp Asp Val Asp Cys Thr Leu Val Glu Lys385 390
395 400 Arg Val Leu Ala Leu Gly Gly Arg Gly Pro Gly
Gly Arg Pro His Phe 405 410
415 Leu Thr Gln Leu His Ser Thr Phe Gln Thr Pro Asp Arg Leu Tyr Phe
420 425 430 Val Met Glu
Tyr Val Thr Gly Gly Asp Leu Met Tyr His Ile Gln Gln 435
440 445 Leu Gly Lys Phe Lys Glu Pro His
Ala Ala Phe Tyr Ala Ala Glu Ile 450 455
460 Ala Ile Gly Leu Phe Phe Leu His Asn Gln Gly Ile Ile
Tyr Arg Asp465 470 475
480 Leu Lys Leu Asp Asn Val Met Leu Asp Ala Glu Gly His Ile Lys Ile
485 490 495 Thr Asp Phe Gly
Met Cys Lys Glu Asn Val Phe Pro Gly Thr Thr Thr 500
505 510 Arg Thr Phe Cys Gly Thr Pro Asp Tyr
Ile Ala Pro Glu Ile Ile Ala 515 520
525 Tyr Gln Pro Tyr Gly Lys Ser Val Asp Trp Trp Ser Phe Gly
Val Leu 530 535 540
Leu Tyr Glu Met Leu Ala Gly Gln Pro Pro Phe Asp Gly Glu Asp Glu545
550 555 560 Glu Glu Leu Phe Gln
Ala Ile Met Glu Gln Thr Val Thr Tyr Pro Lys 565
570 575 Ser Leu Ser Arg Glu Ala Val Ala Ile Cys
Lys Gly Phe Leu Thr Lys 580 585
590 His Pro Gly Lys Arg Leu Gly Ser Gly Pro Asp Gly Glu Pro Thr
Ile 595 600 605 Arg
Ala His Gly Phe Phe Arg Trp Ile Asp Trp Glu Arg Leu Glu Arg 610
615 620 Leu Glu Ile Pro Pro Pro
Phe Arg Pro Arg Pro Cys Gly Arg Ser Gly625 630
635 640 Glu Asn Phe Asp Lys Phe Phe Thr Arg Ala Ala
Pro Ala Leu Thr Pro 645 650
655 Pro Asp Arg Leu Val Leu Ala Ser Ile Asp Gln Ala Asp Phe Gln Gly
660 665 670 Phe Thr Tyr
Val Asn Pro Asp Phe Val His Pro Asp Ala Arg Ser Pro 675
680 685 Thr Ser Pro Val Pro Val Pro Val
Met 690 695 168676PRTHomo sapiens 168Met Ala
Pro Phe Leu Arg Ile Ala Phe Asn Ser Tyr Glu Leu Gly Ser1 5
10 15 Leu Gln Ala Glu Asp Glu Ala
Asn Gln Pro Phe Cys Ala Val Lys Met 20 25
30 Lys Glu Ala Leu Ser Thr Glu Arg Gly Lys Thr Leu
Val Gln Lys Lys 35 40 45
Pro Thr Met Tyr Pro Glu Trp Lys Ser Thr Phe Asp Ala His Ile Tyr
50 55 60 Glu Gly Arg
Val Ile Gln Ile Val Leu Met Arg Ala Ala Glu Glu Pro65 70
75 80 Val Ser Glu Val Thr Val Gly Val
Ser Val Leu Ala Glu Arg Cys Lys 85 90
95 Lys Asn Asn Gly Lys Ala Glu Phe Trp Leu Asp Leu Gln
Pro Gln Ala 100 105 110
Lys Val Leu Met Ser Val Gln Tyr Phe Leu Glu Asp Val Asp Cys Lys
115 120 125 Gln Ser Met Arg
Ser Glu Asp Glu Ala Lys Phe Pro Thr Met Asn Arg 130
135 140 Arg Gly Ala Ile Lys Gln Ala Lys
Ile His Tyr Ile Lys Asn His Glu145 150
155 160 Phe Ile Ala Thr Phe Phe Gly Gln Pro Thr Phe Cys
Ser Val Cys Lys 165 170
175 Asp Phe Val Trp Gly Leu Asn Lys Gln Gly Tyr Lys Cys Arg Gln Cys
180 185 190 Asn Ala Ala
Ile His Lys Lys Cys Ile Asp Lys Ile Ile Gly Arg Cys 195
200 205 Thr Gly Thr Ala Ala Asn Ser Arg
Asp Thr Ile Phe Gln Lys Glu Arg 210 215
220 Phe Asn Ile Asp Met Pro His Arg Phe Lys Val His Asn
Tyr Met Ser225 230 235
240 Pro Thr Phe Cys Asp His Cys Gly Ser Leu Leu Trp Gly Leu Val Lys
245 250 255 Gln Gly Leu Lys
Cys Glu Asp Cys Gly Met Asn Val His His Lys Cys 260
265 270 Arg Glu Lys Val Ala Asn Leu Cys Gly
Ile Asn Gln Lys Leu Leu Ala 275 280
285 Glu Ala Leu Asn Gln Val Thr Gln Arg Ala Ser Arg Arg Ser
Asp Ser 290 295 300
Ala Ser Ser Glu Pro Val Gly Ile Tyr Gln Gly Phe Glu Lys Lys Thr305
310 315 320 Gly Val Ala Gly Glu
Asp Met Gln Asp Asn Ser Gly Thr Tyr Gly Lys 325
330 335 Ile Trp Glu Gly Ser Ser Lys Cys Asn Ile
Asn Asn Phe Ile Phe His 340 345
350 Lys Val Leu Gly Lys Gly Ser Phe Gly Lys Val Leu Leu Gly Glu
Leu 355 360 365 Lys
Gly Arg Gly Glu Tyr Phe Ala Ile Lys Ala Leu Lys Lys Asp Val 370
375 380 Val Leu Ile Asp Asp Asp
Val Glu Cys Thr Met Val Glu Lys Arg Val385 390
395 400 Leu Thr Leu Ala Ala Glu Asn Pro Phe Leu Thr
His Leu Ile Cys Thr 405 410
415 Phe Gln Thr Lys Asp His Leu Phe Phe Val Met Glu Phe Leu Asn Gly
420 425 430 Gly Asp Leu
Met Tyr His Ile Gln Asp Lys Gly Arg Phe Glu Leu Tyr 435
440 445 Arg Ala Thr Phe Tyr Ala Ala Glu
Ile Met Cys Gly Leu Gln Phe Leu 450 455
460 His Ser Lys Gly Ile Ile Tyr Arg Asp Leu Lys Leu Asp
Asn Val Leu465 470 475
480 Leu Asp Arg Asp Gly His Ile Lys Ile Ala Asp Phe Gly Met Cys Lys
485 490 495 Glu Asn Ile Phe
Gly Glu Ser Arg Ala Ser Thr Phe Cys Gly Thr Pro 500
505 510 Asp Tyr Ile Ala Pro Glu Ile Leu Gln
Gly Leu Lys Tyr Thr Phe Ser 515 520
525 Val Asp Trp Trp Ser Phe Gly Val Leu Leu Tyr Glu Met Leu
Ile Gly 530 535 540
Gln Ser Pro Phe His Gly Asp Asp Glu Asp Glu Leu Phe Glu Ser Ile545
550 555 560 Arg Val Asp Thr Pro
His Tyr Pro Arg Trp Ile Thr Lys Glu Ser Lys 565
570 575 Asp Ile Leu Glu Lys Leu Phe Glu Arg Glu
Pro Thr Lys Arg Leu Gly 580 585
590 Val Thr Gly Asn Ile Lys Ile His Pro Phe Phe Lys Thr Ile Asn
Trp 595 600 605 Thr
Leu Leu Glu Lys Arg Arg Leu Glu Pro Pro Phe Arg Pro Lys Val 610
615 620 Lys Ser Pro Arg Asp Tyr
Ser Asn Phe Asp Gln Glu Phe Leu Asn Glu625 630
635 640 Lys Ala Arg Leu Ser Tyr Ser Asp Lys Asn Leu
Ile Asp Ser Met Asp 645 650
655 Gln Ser Ala Phe Ala Gly Phe Ser Phe Val Asn Pro Lys Phe Glu His
660 665 670 Leu Leu Glu
Asp 675 169737PRTHomo sapiens 169Met Val Val Phe Asn Gly Leu
Leu Lys Ile Lys Ile Cys Glu Ala Val1 5 10
15 Ser Leu Lys Pro Thr Ala Trp Ser Leu Arg His Ala
Val Gly Pro Arg 20 25 30
Pro Gln Thr Phe Leu Leu Asp Pro Tyr Ile Ala Leu Asn Val Asp Asp
35 40 45 Ser Arg Ile Gly
Gln Thr Ala Thr Lys Gln Lys Thr Asn Ser Pro Ala 50 55
60 Trp His Asp Glu Phe Val Thr Asp Val
Cys Asn Gly Arg Lys Ile Glu65 70 75
80 Leu Ala Val Phe His Asp Ala Pro Ile Gly Tyr Asp Asp Phe
Val Ala 85 90 95
Asn Cys Thr Ile Gln Phe Glu Glu Leu Leu Gln Asn Gly Ser Arg His
100 105 110 Phe Glu Asp Trp Ile
Asp Leu Glu Pro Glu Gly Arg Val Tyr Val Ile 115
120 125 Ile Asp Leu Ser Gly Ser Ser Gly Glu
Ala Pro Lys Asp Asn Glu Glu 130 135
140 Arg Val Phe Arg Glu Arg Met Arg Pro Arg Lys Arg Gln
Gly Ala Val145 150 155
160 Arg Arg Arg Val His Gln Val Asn Gly His Lys Phe Met Ala Thr Tyr
165 170 175 Leu Arg Gln Pro
Thr Tyr Cys Ser His Cys Arg Asp Phe Ile Trp Gly 180
185 190 Val Ile Gly Lys Gln Gly Tyr Gln Cys
Gln Val Cys Thr Cys Val Val 195 200
205 His Lys Arg Cys His Glu Leu Ile Ile Thr Lys Cys Ala Gly
Leu Lys 210 215 220
Lys Gln Glu Thr Pro Asp Gln Val Gly Ser Gln Arg Phe Ser Val Asn225
230 235 240 Met Pro His Lys Phe
Gly Ile His Asn Tyr Lys Val Pro Thr Phe Cys 245
250 255 Asp His Cys Gly Ser Leu Leu Trp Gly Leu
Leu Arg Gln Gly Leu Gln 260 265
270 Cys Lys Val Cys Lys Met Asn Val His Arg Arg Cys Glu Thr Asn
Val 275 280 285 Ala
Pro Asn Cys Gly Val Asp Ala Arg Gly Ile Ala Lys Val Leu Ala 290
295 300 Asp Leu Gly Val Thr Pro
Asp Lys Ile Thr Asn Ser Gly Gln Arg Arg305 310
315 320 Lys Lys Leu Ile Ala Gly Ala Glu Ser Pro Gln
Pro Ala Ser Gly Ser 325 330
335 Ser Pro Ser Glu Glu Asp Arg Ser Lys Ser Ala Pro Thr Ser Pro Cys
340 345 350 Asp Gln Glu
Ile Lys Glu Leu Glu Asn Asn Ile Arg Lys Ala Leu Ser 355
360 365 Phe Asp Asn Arg Gly Glu Glu His
Arg Ala Ala Ser Ser Pro Asp Gly 370 375
380 Gln Leu Met Ser Pro Gly Glu Asn Gly Glu Val Arg Gln
Gly Gln Ala385 390 395
400 Lys Arg Leu Gly Leu Asp Glu Phe Asn Phe Ile Lys Val Leu Gly Lys
405 410 415 Gly Ser Phe Gly
Lys Val Met Leu Ala Glu Leu Lys Gly Lys Asp Glu 420
425 430 Val Tyr Ala Val Lys Val Leu Lys Lys
Asp Val Ile Leu Gln Asp Asp 435 440
445 Asp Val Asp Cys Thr Met Thr Glu Lys Arg Ile Leu Ala Leu
Ala Arg 450 455 460
Lys His Pro Tyr Leu Thr Gln Leu Tyr Cys Cys Phe Gln Thr Lys Asp465
470 475 480 Arg Leu Phe Phe Val
Met Glu Tyr Val Asn Gly Gly Asp Leu Met Phe 485
490 495 Gln Ile Gln Arg Ser Arg Lys Phe Asp Glu
Pro Arg Ser Arg Phe Tyr 500 505
510 Ala Ala Glu Val Thr Ser Ala Leu Met Phe Leu His Gln His Gly
Val 515 520 525 Ile
Tyr Arg Asp Leu Lys Leu Asp Asn Ile Leu Leu Asp Ala Glu Gly 530
535 540 His Cys Lys Leu Ala Asp
Phe Gly Met Cys Lys Glu Gly Ile Leu Asn545 550
555 560 Gly Val Thr Thr Thr Thr Phe Cys Gly Thr Pro
Asp Tyr Ile Ala Pro 565 570
575 Glu Ile Leu Gln Glu Leu Glu Tyr Gly Pro Ser Val Asp Trp Trp Ala
580 585 590 Leu Gly Val
Leu Met Tyr Glu Met Met Ala Gly Gln Pro Pro Phe Glu 595
600 605 Ala Asp Asn Glu Asp Asp Leu Phe
Glu Ser Ile Leu His Asp Asp Val 610 615
620 Leu Tyr Pro Val Trp Leu Ser Lys Glu Ala Val Ser Ile
Leu Lys Ala625 630 635
640 Phe Met Thr Lys Asn Pro His Lys Arg Leu Gly Cys Val Ala Ser Gln
645 650 655 Asn Gly Glu Asp
Ala Ile Lys Gln His Pro Phe Phe Lys Glu Ile Asp 660
665 670 Trp Val Leu Leu Glu Gln Lys Lys Ile
Lys Pro Pro Phe Lys Pro Arg 675 680
685 Ile Lys Thr Lys Arg Asp Val Asn Asn Phe Asp Gln Asp Phe
Thr Arg 690 695 700
Glu Glu Pro Val Leu Thr Leu Val Asp Glu Ala Ile Val Lys Gln Ile705
710 715 720 Asn Gln Glu Glu Phe
Lys Gly Phe Ser Tyr Phe Gly Glu Asp Leu Met 725
730 735 Pro 170682PRTHomo sapiens 170Met Ser Ser
Gly Thr Met Lys Phe Asn Gly Tyr Leu Arg Val Arg Ile1 5
10 15 Gly Glu Ala Val Gly Leu Gln Pro
Thr Arg Trp Ser Leu Arg His Ser 20 25
30 Leu Phe Lys Lys Gly His Gln Leu Leu Asp Pro Tyr Leu
Thr Val Ser 35 40 45
Val Asp Gln Val Arg Val Gly Gln Thr Ser Thr Lys Gln Lys Thr Asn 50
55 60 Lys Pro Thr Tyr Asn
Glu Glu Phe Cys Ala Asn Val Thr Asp Gly Gly65 70
75 80 His Leu Glu Leu Ala Val Phe His Glu Thr
Pro Leu Gly Tyr Asp Phe 85 90
95 Val Ala Asn Cys Thr Leu Gln Phe Gln Glu Leu Val Gly Thr Thr
Gly 100 105 110 Ala
Ser Asp Thr Phe Glu Gly Trp Val Asp Leu Glu Pro Glu Gly Lys 115
120 125 Val Phe Val Val Ile Thr
Leu Thr Gly Ser Phe Thr Glu Ala Thr Leu 130 135
140 Gln Arg Asp Arg Ile Phe Lys His Phe Thr Arg
Lys Arg Gln Arg Ala145 150 155
160 Met Arg Arg Arg Val His Gln Ile Asn Gly His Lys Phe Met Ala Thr
165 170 175 Tyr Leu Arg
Gln Pro Thr Tyr Cys Ser His Cys Arg Glu Phe Ile Trp 180
185 190 Gly Val Phe Gly Lys Gln Gly Tyr
Gln Cys Gln Val Cys Thr Cys Val 195 200
205 Val His Lys Arg Cys His His Leu Ile Val Thr Ala Cys
Thr Cys Gln 210 215 220
Asn Asn Ile Asn Lys Val Asp Ser Lys Ile Ala Glu Gln Arg Phe Gly225
230 235 240 Ile Asn Ile Pro His
Lys Phe Ser Ile His Asn Tyr Lys Val Pro Thr 245
250 255 Phe Cys Asp His Cys Gly Ser Leu Leu Trp
Gly Ile Met Arg Gln Gly 260 265
270 Leu Gln Cys Lys Ile Cys Lys Met Asn Val His Ile Arg Cys Gln
Ala 275 280 285 Asn
Val Ala Pro Asn Cys Gly Val Asn Ala Val Glu Leu Ala Lys Thr 290
295 300 Leu Ala Gly Met Gly Leu
Gln Pro Gly Asn Ile Ser Pro Thr Ser Lys305 310
315 320 Leu Val Ser Arg Ser Thr Leu Arg Arg Gln Gly
Lys Glu Ser Ser Lys 325 330
335 Glu Gly Asn Gly Ile Gly Val Asn Ser Ser Asn Arg Leu Gly Ile Asp
340 345 350 Asn Phe Glu
Phe Ile Arg Val Leu Gly Lys Gly Ser Phe Gly Lys Val 355
360 365 Met Leu Ala Arg Val Lys Glu Thr
Gly Asp Leu Tyr Ala Val Lys Val 370 375
380 Leu Lys Lys Asp Val Ile Leu Leu Asp Asp Asp Val Glu
Cys Thr Met385 390 395
400 Thr Glu Lys Arg Ile Leu Ser Leu Ala Arg Asn His Pro Phe Leu Thr
405 410 415 Gln Leu Phe Cys
Cys Phe Gln Thr Pro Asp Arg Leu Phe Phe Val Met 420
425 430 Glu Phe Val Asn Gly Gly Asp Leu Met
Phe His Ile Gln Lys Ser Arg 435 440
445 Arg Phe Asp Glu Ala Arg Ala Arg Phe Tyr Ala Ala Glu Ile
Ile Ser 450 455 460
Ala Leu Met Phe Leu His Asp Lys Gly Ile Ile Tyr Arg Asp Leu Lys465
470 475 480 Leu Asp Asn Val Leu
Leu Asp His Glu Gly His Cys Lys Leu Ala Asp 485
490 495 Phe Gly Met Cys Lys Glu Gly Ile Cys Asn
Gly Val Thr Thr Ala Thr 500 505
510 Phe Cys Gly Thr Pro Asp Tyr Ile Ala Pro Glu Ile Leu Gln Glu
Met 515 520 525 Leu
Tyr Gly Pro Ala Val Asp Trp Trp Ala Met Gly Val Leu Leu Tyr 530
535 540 Glu Met Leu Cys Gly His
Ala Pro Phe Glu Ala Glu Asn Glu Asp Asp545 550
555 560 Leu Phe Glu Ala Ile Leu Asn Asp Glu Val Val
Tyr Pro Thr Trp Leu 565 570
575 His Glu Asp Ala Thr Gly Ile Leu Lys Ser Phe Met Thr Lys Asn Pro
580 585 590 Thr Met Arg
Leu Gly Ser Leu Thr Gln Gly Gly Glu His Ala Ile Leu 595
600 605 Arg His Pro Phe Phe Lys Glu Ile
Asp Trp Ala Gln Leu Asn His Arg 610 615
620 Gln Ile Glu Pro Pro Phe Arg Pro Arg Ile Lys Ser Arg
Glu Asp Val625 630 635
640 Ser Asn Phe Asp Pro Asp Phe Ile Lys Glu Glu Pro Val Leu Thr Pro
645 650 655 Ile Asp Glu Gly
His Leu Pro Met Ile Asn Gln Asp Glu Phe Arg Asn 660
665 670 Phe Ser Tyr Val Ser Pro Glu Leu Gln
Pro 675 680 171706PRTHomo sapiens 171Met
Ser Pro Phe Leu Arg Ile Gly Leu Ser Asn Phe Asp Cys Gly Ser1
5 10 15 Cys Gln Ser Cys Gln Gly
Glu Ala Val Asn Pro Tyr Cys Ala Val Leu 20 25
30 Val Lys Glu Tyr Val Glu Ser Glu Asn Gly Gln
Met Tyr Ile Gln Lys 35 40 45
Lys Pro Thr Met Tyr Pro Pro Trp Asp Ser Thr Phe Asp Ala His Ile
50 55 60 Asn Lys Gly
Arg Val Met Gln Ile Ile Val Lys Gly Lys Asn Val Asp65 70
75 80 Leu Ile Ser Glu Thr Thr Val Glu
Leu Tyr Ser Leu Ala Glu Arg Cys 85 90
95 Arg Lys Asn Asn Gly Lys Thr Glu Ile Trp Leu Glu Leu
Lys Pro Gln 100 105 110
Gly Arg Met Leu Met Asn Ala Arg Tyr Phe Leu Glu Met Ser Asp Thr
115 120 125 Lys Asp Met Asn
Glu Phe Glu Thr Glu Gly Phe Phe Ala Leu His Gln 130
135 140 Arg Arg Gly Ala Ile Lys Gln Ala
Lys Val His His Val Lys Cys His145 150
155 160 Glu Phe Thr Ala Thr Phe Phe Pro Gln Pro Thr Phe
Cys Ser Val Cys 165 170
175 His Glu Phe Val Trp Gly Leu Asn Lys Gln Gly Tyr Gln Cys Arg Gln
180 185 190 Cys Asn Ala
Ala Ile His Lys Lys Cys Ile Asp Lys Val Ile Ala Lys 195
200 205 Cys Thr Gly Ser Ala Ile Asn Ser
Arg Glu Thr Met Phe His Lys Glu 210 215
220 Arg Phe Lys Ile Asp Met Pro His Arg Phe Lys Val Tyr
Asn Tyr Lys225 230 235
240 Ser Pro Thr Phe Cys Glu His Cys Gly Thr Leu Leu Trp Gly Leu Ala
245 250 255 Arg Gln Gly Leu
Lys Cys Asp Ala Cys Gly Met Asn Val His His Arg 260
265 270 Cys Gln Thr Lys Val Ala Asn Leu Cys
Gly Ile Asn Gln Lys Leu Met 275 280
285 Ala Glu Ala Leu Ala Met Ile Glu Ser Thr Gln Gln Ala Arg
Cys Leu 290 295 300
Arg Asp Thr Glu Gln Ile Phe Arg Glu Gly Pro Val Glu Ile Gly Leu305
310 315 320 Pro Cys Ser Ile Lys
Asn Glu Ala Arg Pro Pro Cys Leu Pro Thr Pro 325
330 335 Gly Lys Arg Glu Pro Gln Gly Ile Ser Trp
Glu Ser Pro Leu Asp Glu 340 345
350 Val Asp Lys Met Cys His Leu Pro Glu Pro Glu Leu Asn Lys Glu
Arg 355 360 365 Pro
Ser Leu Gln Ile Lys Leu Lys Ile Glu Asp Phe Ile Leu His Lys 370
375 380 Met Leu Gly Lys Gly Ser
Phe Gly Lys Val Phe Leu Ala Glu Phe Lys385 390
395 400 Lys Thr Asn Gln Phe Phe Ala Ile Lys Ala Leu
Lys Lys Asp Val Val 405 410
415 Leu Met Asp Asp Asp Val Glu Cys Thr Met Val Glu Lys Arg Val Leu
420 425 430 Ser Leu Ala
Trp Glu His Pro Phe Leu Thr His Met Phe Cys Thr Phe 435
440 445 Gln Thr Lys Glu Asn Leu Phe Phe
Val Met Glu Tyr Leu Asn Gly Gly 450 455
460 Asp Leu Met Tyr His Ile Gln Ser Cys His Lys Phe Asp
Leu Ser Arg465 470 475
480 Ala Thr Phe Tyr Ala Ala Glu Ile Ile Leu Gly Leu Gln Phe Leu His
485 490 495 Ser Lys Gly Ile
Val Tyr Arg Asp Leu Lys Leu Asp Asn Ile Leu Leu 500
505 510 Asp Lys Asp Gly His Ile Lys Ile Ala
Asp Phe Gly Met Cys Lys Glu 515 520
525 Asn Met Leu Gly Asp Ala Lys Thr Asn Thr Phe Cys Gly Thr
Pro Asp 530 535 540
Tyr Ile Ala Pro Glu Ile Leu Leu Gly Gln Lys Tyr Asn His Ser Val545
550 555 560 Asp Trp Trp Ser Phe
Gly Val Leu Leu Tyr Glu Met Leu Ile Gly Gln 565
570 575 Ser Pro Phe His Gly Gln Asp Glu Glu Glu
Leu Phe His Ser Ile Arg 580 585
590 Met Asp Asn Pro Phe Tyr Pro Arg Trp Leu Glu Lys Glu Ala Lys
Asp 595 600 605 Leu
Leu Val Lys Leu Phe Val Arg Glu Pro Glu Lys Arg Leu Gly Val 610
615 620 Arg Gly Asp Ile Arg Gln
His Pro Leu Phe Arg Glu Ile Asn Trp Glu625 630
635 640 Glu Leu Glu Arg Lys Glu Ile Asp Pro Pro Phe
Arg Pro Lys Val Lys 645 650
655 Ser Pro Phe Asp Cys Ser Asn Phe Asp Lys Glu Phe Leu Asn Glu Lys
660 665 670 Pro Arg Leu
Ser Phe Ala Asp Arg Ala Leu Ile Asn Ser Met Asp Gln 675
680 685 Asn Met Phe Arg Asn Phe Ser Phe
Met Asn Pro Gly Met Glu Arg Leu 690 695
700 Glu Ser705 172587PRTHomo sapiens 172Met Ser His
Thr Val Ala Gly Gly Gly Ser Gly Asp His Ser His Gln1 5
10 15 Val Arg Val Lys Ala Tyr Tyr Arg
Gly Asp Ile Met Ile Thr His Phe 20 25
30 Glu Pro Ser Ile Ser Phe Glu Gly Leu Cys Asn Glu Val
Arg Asp Met 35 40 45
Cys Ser Phe Asp Asn Glu Gln Leu Phe Thr Met Lys Trp Ile Asp Glu 50
55 60 Glu Gly Asp Pro Cys
Thr Val Ser Ser Gln Leu Glu Leu Glu Glu Ala65 70
75 80 Phe Arg Leu Tyr Glu Leu Asn Lys Asp Ser
Glu Leu Leu Ile His Val 85 90
95 Phe Pro Cys Val Pro Glu Arg Pro Gly Met Pro Cys Pro Gly Glu
Asp 100 105 110 Lys
Ser Ile Tyr Arg Arg Gly Ala Arg Arg Trp Arg Lys Leu Tyr Cys 115
120 125 Ala Asn Gly His Thr Phe
Gln Ala Lys Arg Phe Asn Arg Arg Ala His 130 135
140 Cys Ala Ile Cys Thr Asp Arg Ile Trp Gly Leu
Gly Arg Gln Gly Tyr145 150 155
160 Lys Cys Ile Asn Cys Lys Leu Leu Val His Lys Lys Cys His Lys Leu
165 170 175 Val Thr Ile
Glu Cys Gly Arg His Ser Leu Pro Gln Glu Pro Val Met 180
185 190 Pro Met Asp Gln Ser Ser Met His
Ser Asp His Ala Gln Thr Val Ile 195 200
205 Pro Tyr Asn Pro Ser Ser His Glu Ser Leu Asp Gln Val
Gly Glu Glu 210 215 220
Lys Glu Ala Met Asn Thr Arg Glu Ser Gly Lys Ala Ser Ser Ser Leu225
230 235 240 Gly Leu Gln Asp Phe
Asp Leu Leu Arg Val Ile Gly Arg Gly Ser Tyr 245
250 255 Ala Lys Val Leu Leu Val Arg Leu Lys Lys
Thr Asp Arg Ile Tyr Ala 260 265
270 Met Lys Val Val Lys Lys Glu Leu Val Asn Asp Asp Glu Asp Ile
Asp 275 280 285 Trp
Val Gln Thr Glu Lys His Val Phe Glu Gln Ala Ser Asn His Pro 290
295 300 Phe Leu Val Gly Leu His
Ser Cys Phe Gln Thr Glu Ser Arg Leu Phe305 310
315 320 Phe Val Ile Glu Tyr Val Asn Gly Gly Asp Leu
Met Phe His Met Gln 325 330
335 Arg Gln Arg Lys Leu Pro Glu Glu His Ala Arg Phe Tyr Ser Ala Glu
340 345 350 Ile Ser Leu
Ala Leu Asn Tyr Leu His Glu Arg Gly Ile Ile Tyr Arg 355
360 365 Asp Leu Lys Leu Asp Asn Val Leu
Leu Asp Ser Glu Gly His Ile Lys 370 375
380 Leu Thr Asp Tyr Gly Met Cys Lys Glu Gly Leu Arg Pro
Gly Asp Thr385 390 395
400 Thr Ser Thr Phe Cys Gly Thr Pro Asn Tyr Ile Ala Pro Glu Ile Leu
405 410 415 Arg Gly Glu Asp
Tyr Gly Phe Ser Val Asp Trp Trp Ala Leu Gly Val 420
425 430 Leu Met Phe Glu Met Met Ala Gly Arg
Ser Pro Phe Asp Ile Val Gly 435 440
445 Ser Ser Asp Asn Pro Asp Gln Asn Thr Glu Asp Tyr Leu Phe
Gln Val 450 455 460
Ile Leu Glu Lys Gln Ile Arg Ile Pro Arg Ser Leu Ser Val Lys Ala465
470 475 480 Ala Ser Val Leu Lys
Ser Phe Leu Asn Lys Asp Pro Lys Glu Arg Leu 485
490 495 Gly Cys His Pro Gln Thr Gly Phe Ala Asp
Ile Gln Gly His Pro Phe 500 505
510 Phe Arg Asn Val Asp Trp Asp Met Met Glu Gln Lys Gln Val Val
Pro 515 520 525 Pro
Phe Lys Pro Asn Ile Ser Gly Glu Phe Gly Leu Asp Asn Phe Asp 530
535 540 Ser Gln Phe Thr Asn Glu
Pro Val Gln Leu Thr Pro Asp Asp Asp Asp545 550
555 560 Ile Val Arg Lys Ile Asp Gln Ser Glu Phe Glu
Gly Phe Glu Tyr Ile 565 570
575 Asn Pro Leu Leu Met Ser Ala Glu Glu Cys Val 580
585 173912PRTHomo sapiens 173Met Ser Ala Pro Pro Val
Leu Arg Pro Pro Ser Pro Leu Leu Pro Val1 5
10 15 Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Leu
Val Pro Gly Ser Gly 20 25 30
Pro Gly Pro Ala Pro Phe Leu Ala Pro Val Ala Ala Pro Val Gly Gly
35 40 45 Ile Ser Phe
His Leu Gln Ile Gly Leu Ser Arg Glu Pro Val Leu Leu 50
55 60 Leu Gln Asp Ser Ser Gly Asp Tyr
Ser Leu Ala His Val Arg Glu Met65 70 75
80 Ala Cys Ser Ile Val Asp Gln Lys Phe Pro Glu Cys Gly
Phe Tyr Gly 85 90 95
Met Tyr Asp Lys Ile Leu Leu Phe Arg His Asp Pro Thr Ser Glu Asn
100 105 110 Ile Leu Gln Leu Val
Lys Ala Ala Ser Asp Ile Gln Glu Gly Asp Leu 115
120 125 Ile Glu Val Val Leu Ser Arg Ser Ala
Thr Phe Glu Asp Phe Gln Ile 130 135
140 Arg Pro His Ala Leu Phe Val His Ser Tyr Arg Ala Pro
Ala Phe Cys145 150 155
160 Asp His Cys Gly Glu Met Leu Trp Gly Leu Val Arg Gln Gly Leu Lys
165 170 175 Cys Glu Gly Cys
Gly Leu Asn Tyr His Lys Arg Cys Ala Phe Lys Ile 180
185 190 Pro Asn Asn Cys Ser Gly Val Arg Arg
Arg Arg Leu Ser Asn Val Ser 195 200
205 Leu Thr Gly Val Ser Thr Ile Arg Thr Ser Ser Ala Glu Leu
Ser Thr 210 215 220
Ser Ala Pro Asp Glu Pro Leu Leu Gln Lys Ser Pro Ser Glu Ser Phe225
230 235 240 Ile Gly Arg Glu Lys
Arg Ser Asn Ser Gln Ser Tyr Ile Gly Arg Pro 245
250 255 Ile His Leu Asp Lys Ile Leu Met Ser Lys
Val Lys Val Pro His Thr 260 265
270 Phe Val Ile His Ser Tyr Thr Arg Pro Thr Val Cys Gln Tyr Cys
Lys 275 280 285 Lys
Leu Leu Lys Gly Leu Phe Arg Gln Gly Leu Gln Cys Lys Asp Cys 290
295 300 Arg Phe Asn Cys His Lys
Arg Cys Ala Pro Lys Val Pro Asn Asn Cys305 310
315 320 Leu Gly Glu Val Thr Ile Asn Gly Asp Leu Leu
Ser Pro Gly Ala Glu 325 330
335 Ser Asp Val Val Met Glu Glu Gly Ser Asp Asp Asn Asp Ser Glu Arg
340 345 350 Asn Ser Gly
Leu Met Asp Asp Met Glu Glu Ala Met Val Gln Asp Ala 355
360 365 Glu Met Ala Met Ala Glu Cys Gln
Asn Asp Ser Gly Glu Met Gln Asp 370 375
380 Pro Asp Pro Asp His Glu Asp Ala Asn Arg Thr Ile Ser
Pro Ser Thr385 390 395
400 Ser Asn Asn Ile Pro Leu Met Arg Val Val Gln Ser Val Lys His Thr
405 410 415 Lys Arg Lys Ser
Ser Thr Val Met Lys Glu Gly Trp Met Val His Tyr 420
425 430 Thr Ser Lys Asp Thr Leu Arg Lys Arg
His Tyr Trp Arg Leu Asp Ser 435 440
445 Lys Cys Ile Thr Leu Phe Gln Asn Asp Thr Gly Ser Arg Tyr
Tyr Lys 450 455 460
Glu Ile Pro Leu Ser Glu Ile Leu Ser Leu Glu Pro Val Lys Thr Ser465
470 475 480 Ala Leu Ile Pro Asn
Gly Ala Asn Pro His Cys Phe Glu Ile Thr Thr 485
490 495 Ala Asn Val Val Tyr Tyr Val Gly Glu Asn
Val Val Asn Pro Ser Ser 500 505
510 Pro Ser Pro Asn Asn Ser Val Leu Thr Ser Gly Val Gly Ala Asp
Val 515 520 525 Ala
Arg Met Trp Glu Ile Ala Ile Gln His Ala Leu Met Pro Val Ile 530
535 540 Pro Lys Gly Ser Ser Val
Gly Thr Gly Thr Asn Leu His Arg Asp Ile545 550
555 560 Ser Val Ser Ile Ser Val Ser Asn Cys Gln Ile
Gln Glu Asn Val Asp 565 570
575 Ile Ser Thr Val Tyr Gln Ile Phe Pro Asp Glu Val Leu Gly Ser Gly
580 585 590 Gln Phe Gly
Ile Val Tyr Gly Gly Lys His Arg Lys Thr Gly Arg Asp 595
600 605 Val Ala Ile Lys Ile Ile Asp Lys
Leu Arg Phe Pro Thr Lys Gln Glu 610 615
620 Ser Gln Leu Arg Asn Glu Val Ala Ile Leu Gln Asn Leu
His His Pro625 630 635
640 Gly Val Val Asn Leu Glu Cys Met Phe Glu Thr Pro Glu Arg Val Phe
645 650 655 Val Val Met Glu
Lys Leu His Gly Asp Met Leu Glu Met Ile Leu Ser 660
665 670 Ser Glu Lys Gly Arg Leu Pro Glu His
Ile Thr Lys Phe Leu Ile Thr 675 680
685 Gln Ile Leu Val Ala Leu Arg His Leu His Phe Lys Asn Ile
Val His 690 695 700
Cys Asp Leu Lys Pro Glu Asn Val Leu Leu Ala Ser Ala Asp Pro Phe705
710 715 720 Pro Gln Val Lys Leu
Cys Asp Phe Gly Phe Ala Arg Ile Ile Gly Glu 725
730 735 Lys Ser Phe Arg Arg Ser Val Val Gly Thr
Pro Ala Tyr Leu Ala Pro 740 745
750 Glu Val Leu Arg Asn Lys Gly Tyr Asn Arg Ser Leu Asp Met Trp
Ser 755 760 765 Val
Gly Val Ile Ile Tyr Val Ser Leu Ser Gly Thr Phe Pro Phe Asn 770
775 780 Glu Asp Glu Asp Ile His
Asp Gln Ile Gln Asn Ala Ala Phe Met Tyr785 790
795 800 Pro Pro Asn Pro Trp Lys Glu Ile Ser His Glu
Ala Ile Asp Leu Ile 805 810
815 Asn Asn Leu Leu Gln Val Lys Met Arg Lys Arg Tyr Ser Val Asp Lys
820 825 830 Thr Leu Ser
His Pro Trp Leu Gln Asp Tyr Gln Thr Trp Leu Asp Leu 835
840 845 Arg Glu Leu Glu Cys Lys Ile Gly
Glu Arg Tyr Ile Thr His Glu Ser 850 855
860 Asp Asp Leu Arg Trp Glu Lys Tyr Ala Gly Glu Gln Arg
Leu Gln Tyr865 870 875
880 Pro Thr His Leu Ile Asn Pro Ser Ala Ser His Ser Asp Thr Pro Glu
885 890 895 Thr Glu Glu Thr
Glu Met Lys Ala Leu Gly Glu Arg Val Ser Ile Leu 900
905 910 17411PRTArtificial Sequencesynthetic
construct 174Xaa Ser Phe Asn Ser Tyr Glu Leu Gly Ser Leu1 5
10 17512PRTArtificial Sequencetransport peptide
175Xaa Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg1 5
10
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