Compositions and methods for treating cardiovascular disease
The invention provides PCSK9 inhibitors, compositions comprising the PCSK9 inhibitors, and methods of identifying and using the PCSK9 inhibitors.
1. A PCSK9 inhibitor that binds an epitope of SEQ ID NO:1, wherein the epitope comprises at least one residue selected from the group consisting of V241, T339, D343, P364, A442, A443, and L444 of SEQ ID NO: 1 selected from compounds of Formula I:
Formula I
(SEQ ID NO: 2)
R 1 -X 1 -X 2 -X 3 -Trp-Asn-Leu-X 4 -X 5 -Ile-Gly-X 6 -R 2 ,
and pharmaceutically acceptable salts thereof; wherein,
R 1 is C 1 -C 4 acyl; or R 1 is absent;
X 1 is an amino acid sequence selected from: TVFTSWEEYLDWV (SEQ ID NO:3) and TAFTSWEEYLDWV (SEQ ID NO: 4); or X 1 is absent;
X 2 is an amino acid sequence comprising 1 to 4 amino acid residues selected from: glycine and serine; or X 2 is an amino acid residue selected from: 5-aminopentanoic acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminonoanoic acid, 10-aminodecanoic acid, and 11-aminoundecanoic acid; or X 2 is absent;
X 3 is an amino acid sequence comprising 1 to 4 amino acid residues selected from: alanine, 2-aminocyclohexane-1-carboxylic acid, arginine, aspartic acid, cysteine, glycine, 3-hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, and tryptophan;
X 4 is an amino acid residue selected from: alanine, 2,3-diaminopropionic acid, glutamine, glycine, lysine, and valine;
X 5 is an amino acid residue selected from: arginine and homo-arginine;
X 6 is an amino acid sequence comprising 1 to 5 amino acid residues selected from:
alanine, arginine, cysteine, glutamic acid, glutamine, glycine, leucine, lysine, phenylalanine, proline, serine, threonine, and tryptophan; or X 6 is absent; and
R 2 is amino; or R 2 is absent.
2. The PCSK9 inhibitor of claim 1 , wherein R 1 is C 1 -C 4 acyl.
3. The PCSK9 inhibitor of claim 2 , wherein R 1 is acetyl.
4. The PCSK9 inhibitor of claim 2 , wherein R 1 is valeryl.
5. The PCSK9 inhibitor of claim 1 , wherein R 1 is absent.
6. The PCSK9 inhibitor of claim 1 , wherein X 1 is an amino acid sequence selected from: TVFTSWEEYLDWV (SEQ ID NO: 3) and TAFTSWEEYLDWV (SEQ ID NO: 4).
7. The PCSK9 inhibitor of claim 6 , wherein X 1 is the amino acid sequence TVFTSWEEYLDWV (SEQ ID NO: 3).
8. The PCSK9 inhibitor of claim 6 , wherein X 1 is the amino acid sequence TAFTSWEEYLDWV (SEQ ID NO: 4).
9. The PCSK9 inhibitor of claim 1 , wherein X 1 is absent.
10. The PCSK9 inhibitor of claim 1 , wherein X 2 is an amino acid sequence comprising 1 to 4 amino acid residues selected from: glycine and serine.
11. The PCSK9 inhibitor of claim 10 , wherein X 2 is an amino acid sequence selected from: SG, GSG, GGSG (SEQ ID NO: 11), GSGG (SEQ ID NO: 12), and SGSG (SEQ ID NO: 13).
12. The PCSK9 inhibitor of claim 1 , wherein X 2 is an amino acid residue selected from: 5-aminopentanoic acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminonoanoic acid, 10-aminodecanoic acid, and 11-aminoundecanoic acid.
13. The PCSK9 inhibitor of claim 12 , wherein X 2 is the amino acid residue 6-aminohexanoic acid.
14. The PCSK9 inhibitor of claim 12 , wherein X 2 is the amino acid residue 7-aminoheptanoic acid.
15. The PCSK9 inhibitor of claim 12 , wherein X 2 is the amino acid residue 8-aminooctanoic acid.
16. The PCSK9 inhibitor of claim 1 , wherein X 2 is absent.
17. The PCSK9 inhibitor of claim 1 , wherein X 3 is an amino acid sequence selected from: P, MP, LMP, ALMP (SEQ ID NO: 14), CALP (SEQ ID NO: 15), CFIP (SEQ ID NO: 16), CFLP (SEQ ID NO: 17), CRAP (SEQ ID NO: 18), CRL(Hyp) (SEQ ID NO: 19), CRLP (SEQ ID NO: 20), DAMP (SEQ ID NO: 21), DLAP (SEQ ID NO: 22), and DLMP (SEQ ID NO: 23).
18. The PCSK9 inhibitor of claim 1 , wherein X 4 is the amino acid residue alanine.
19. The PCSK9 inhibitor of claim 1 , wherein X 4 is the amino acid residue 2,3-diaminopropionic acid.
20. The PCSK9 inhibitor of claim 1 , wherein X 4 is the amino acid residue glutamine.
21. The PCSK9 inhibitor of claim 1 , wherein X 4 is the amino acid residue glycine.
22. The PCSK9 inhibitor of claim 1 , wherein X 4 is the amino acid residue lysine.
23. The PCSK9 inhibitor of claim 1 , wherein X 4 is the amino acid residue valine.
24. The PCSK9 inhibitor of claim 1 , wherein X 5 is the amino acid residue arginine.
25. The PCSK9 inhibitor of claim 1 , wherein X 5 is the amino acid residue homo-arginine.
26. The PCSK9 inhibitor of claim 1 , wherein X 6 is an amino acid sequence selected from: L, S, LL, LAR, LGC, LLA, LLC, LLR, LPC, LTR, SQGC (SEQ ID NO: 24), SQCWF (SEQ ID NO: 26), and SQGCW (SEQ ID NO: 27).
27. The PCSK9 inhibitor of claim 1 , wherein X 6 is absent.
28. The PCSK9 inhibitor of claim 1 , wherein R 2 is amino.
29. The PCSK9 inhibitor of claim 1 , wherein R 2 is absent.
30. The PCSK9 inhibitor of claim 1 , selected from the following compounds and pharmaceutically acceptable salts thereof:
(SEQ ID NO: 29)
Ac-TVFTSWEEYLDWV-GSG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 38)
Ac-TVFTSWEEYLDWV-GSG-CWNLGRIGSQGC-NH2;
(SEQ ID NO: 40)
Ac-TVFTSWEEYLDWV-GGSG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 41)
Ac-TVFTSWEEYLDWV-GSGG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 42)
Ac-TVFTSWEEYLDWV-(Aoc)-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 44)
Ac-TVFTSWEEYLDWV-(Ahx)-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 46)
Ac-TVFTSWEEYLDWV-GSG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 47)
Ac-TVFTSWEEYLDWV-GSG-DLMPWNLVRIGLLR-NH2;
(SEQ ID NO: 48)
Ac-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 49)
Ac-GSG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 51)
Ac-TVFTSWEEYLDWV-(Ahp)-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 149)
Ac-TVFTSWEEYLDWV-SGG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 52)
Ac-TVFTSWEEYLDWV-GSGG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 53)
SG-CFIPWNLQRIGLLC-NH2;
(SEQ ID NO: 54)
SG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 55)
SG-DLMPWNLVRIGLLR
(SEQ ID NO: 56)
Ac-SG-CFIPWNLQRIGLLC-NH2;
(SEQ ID NO: 57)
Ac-SG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 58)
Ac-CFIPWNLQRIGLLC-NH2;
(SEQ ID NO: 59)
Ac-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 62)
Ac-DLMPWNLVRIGLLR-NH2;
(SEQ ID NO: 64)
Ac-SG-CRL(Hyp)WNLQRIGLPC-NH2;
(SEQ ID NO: 65)
Ac-TVFTSWEEYLDWV-GSGG-CFLPWNLQRIGLLC-NH2;
(SEQ ID NO: 66)
Ac-CWNLKRIGSQGCW-NH2;
(SEQ ID NO: 67)
Ac-GSG-CWNLKRIGSQGCW-NH2;
(SEQ ID NO: 69)
Ac-DLMAWNLVRIGLLR-NH2;
(SEQ ID NO: 70)
Ac-DLAPWNLVRIGLLR-NH2;
(SEQ ID NO: 71)
Ac-DAMPWNLVRIGLLR-NH2;
(SEQ ID NO: 72)
Ac-ALMPWNLVRIGLLR-NH2;
(SEQ ID NO: 73)
Ac-DLMPWNLVRIGLL-NH2;
(SEQ ID NO: 74)
Ac-DLMPWNLVRIGL-NH2;
(SEQ ID NO: 75)
Ac-DLMPWNLVRIG-NH2;
(SEQ ID NO: 77)
Ac-LMPWNLVRIGLLR-NH2;
(SEQ ID NO: 78)
Ac-MPWNLVRIGLLR-NH2;
(SEQ ID NO: 79)
Ac-PWNLVRIGLLR-NH2;
(SEQ ID NO: 81)
Ac-DLMPWNLVRIGLLA-NH2;
(SEQ ID NO: 82)
Ac-DLMPWNLVRIGLAR-NH2;
(SEQ ID NO: 83)
Ac-DLMPWNLVRIGALR-NH2;
(SEQ ID NO: 87)
Ac-DLMPWNLARIGLLR-NH2;
(SEQ ID NO: 150)
GCLWNLKRIGSQCWF
(SEQ ID NO: 94)
Ac-CRLPWNLKRIGLPC-NH2;
(SEQ ID NO: 95)
Ac-CRLPWNLQRIGLAc-NH2;
(SEQ ID NO: 96)
Ac-CRLPWNLQRIGAPC-NH2;
(SEQ ID NO: 100)
Ac-CRLPWNLARIGLPC-NH2;
(SEQ ID NO: 104)
Ac-CRLAWNLQRIGLPC-NH2;
(SEQ ID NO: 105)
Ac-CRAPWNLQRIGLPC-NH2;
(SEQ ID NO: 106)
Ac-CALPWNLQRIGLPC-NH2;
(SEQ ID NO: 107)
Ac-CRLPWNLQRIGLGC-NH2;
(SEQ ID NO: 108)
Ac-CRLPWNLQRIGGGC-NH2;
(SEQ ID NO: 109)
Ac-CRL(Ach)WNLQRIGLPC-NH2;
(SEQ ID NO: 114)
Ac-GCLWNLKRIGSQCWF-NH2;
(SEQ ID NO: 151)
Ac-GCLWNLARIGSQCWF-NH2;
(SEQ ID NO: 115)
Ac-FCLWNLARIGSQCWF-NH2;
(SEQ ID NO: 152)
GCLWNLKRIGSQCWF-NH2;
(SEQ ID NO: 116)
WCLWNLKRIGSQCWF-NH2;
(SEQ ID NO: 153)
Ac-GCLWNLKRIGSQCWF
(SEQ ID NO: 117)
Ac-WCLWNLKRIGSQCWF
(SEQ ID NO: 118)
Ac-TVFTSWEEYLDWV-(Ahx)-AWNLKRIGS-NH2;
(SEQ ID NO: 119)
Ac-TVFTSWEEYLDWV-(Ahx)-AWNLKRIG-NH2;
(SEQ ID NO: 123)
Ac-FCLWNLKRIGAQCWF-NH2;
(SEQ ID NO: 124)
Ac-GSG-CWNL(Dpr)RIGSQGC-NH2;
(SEQ ID NO: 126)
Ac-CRLPWNLQRIGLpC-NH2;
(SEQ ID NO: 127)
Ac-CRLPWNLQRIGIPC-NH2;
(SEQ ID NO: 130)
Ac-CRLPWNLqRIGLPC-NH2;
(SEQ ID NO: 134)
Ac-CRLpWNLQRIGLPC-NH2;
(SEQ ID NO: 135)
Ac-CR1PWNLQRIGLPC-NH2;
(SEQ ID NO: 136)
Ac-CrLPWNLQRIGLPC-NH2;
(SEQ ID NO: 137)
Ac-cRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 144)
Ac-CRLPWNLQ(homoR)IGLPC-NH2;
and
(SEQ ID NO: 146)
Ac-PWNLVRIGL-NH2.
31. A PCSK9 inhibitor that binds an epitope of SEQ ID NO:1, wherein the epitope comprises at least one residue selected from the group consisting of V241, T339, D343, P364, A442, A443, and L444 of SEQ ID NO: 1 selected from compounds of Formula II:
Formula II
(SEQ ID NO: 154)
R 1 -X 1 -X 2 -X 3 -X 7 -Asn-Leu-X 4 -X 5 -Ile-Gly-X6-R 2 ,
and pharmaceutically acceptable salts thereof;
wherein,
R 1 is selected from: C 1 -C 4 acyl, arylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, and heteroarylcarbonyl; each optionally substituted with one or two substituents each independently selected from:
C 1 -C 4 alkyl;
amino;
aryl, optionally substituted with one or two substituents each independently selected from: C 1 -C 4 alkoxy, amino, halo, and hydroxy;
aryl-C 1 -C 4 alkyl;
arylcarbonyl, optionally substituted with one substituent selected from: C 1 -C 4 alkyl and C 1 -C 4 alkylsulfonyl;
aryloxy, optionally substituted with one or two substituents each independently selected from: C 1 -C 4 acyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, halo, and hydroxy-C 1 -C 4 alkyl;
carboxyamino, optionally substituted with one substituent selected from: aryl-C 1 -C 4 alkyl;
C 3 -C 7 cycloalkyl;
heteroaryl, optionally substituted with one or two substituents each independently selected from: C 1 -C 4 alkyl and amino;
heterocyclyl, optionally substituted with one or two substituents each independently selected from: C 1 -C 4 alkyl, C 1 -C 4 alkylsulfonyl, carboxamide, heteroaryl-C 1 -C 4 alkyl, and oxo;
heterocyclylcarbonyl; and
ureido;
or R 1 is absent;
X 1 is an amino acid sequence selected from: TVFTSWEEYLDWV (SEQ ID NO: 3), TVFTS(W6fl)EEYLDWV (SEQ ID NO: 30), and TAFTSWEEYLDWV (SEQ ID NO: 4); or X 1 is absent;
X 2 is an amino acid sequence comprising 1 to 4 amino acid residues selected from: glycine and serine; or X 2 is an amino acid residue selected from: 5-aminopentanoic acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminonoanoic acid, 10-aminodecanoic acid, and 11-aminoundecanoic acid; or X 2 is absent;
X 3 is an amino acid sequence comprising 1 to 6 amino acid residues selected from: alanine, 2-aminocyclohexane-1-carboxylic acid, arginine, aspartic acid, cysteine, glutamic acid, glycine, 3-hydroxyproline, isoleucine, leucine, methionine, phenylalanine, proline, serine, tryptophan, and tyrosine;
X 4 is an amino acid residue selected from: alanine, 2,3-diaminopropionic acid, glutamine, glycine, lysine, and valine;
X 5 is an amino acid residue selected from: arginine and homo-arginine;
X 6 is an amino acid sequence comprising 1 to 5 amino acid residues selected from: alanine, arginine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, leucine, lysine, phenylalanine, proline, serine, threonine, and tryptophan; or X 6 is absent;
X 7 is an amino acid residue selected from: tryptophan, 6-fluorotryptophan, 6-chlorotryptophan, 6-bromotryptophan, and 6-methyltryptophan; and
R 2 is amino; or R 2 is absent.
32. The PCSK9 inhibitor of claim 31 , wherein R 1 is C 1 -C 4 acyl.
33. The PCSK9 inhibitor of claim 32 , wherein R 1 is acetyl.
34. The PCSK9 inhibitor of claim 32 , wherein R 1 is valeryl.
35. The PCSK9 inhibitor of claim 31 , wherein R 1 is absent.
36. The PCSK9 inhibitor of claim 31 , wherein R 1 is selected from: C 1 -C 4 acyl, arylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, and heteroarylcarbonyl; each optionally substituted with one or two substituents each independently selected from:
C 1 -C 4 alkyl;
amino;
aryl, optionally substituted with one or two substituents each independently selected from: methoxy, amino, fluoro, chloro, and hydroxy;
aryl-C 1 -C 4 alkyl;
arylcarbonyl, optionally substituted with one substituent selected from: methyl and methylsulfonyl;
aryloxy, optionally substituted with one or two substituents each independently selected from: acetyl, methoxy, methyl, ethyl, bromo, and hydroxymethyl;
carboxyamino, optionally substituted with one substituent selected from: phenylmethyl;
C 3 -C 7 cycloalkyl;
heteroaryl, optionally substituted with one or two substituents each independently selected from: methyl and amino;
heterocyclyl, optionally substituted with one or two substituents each independently selected from: methyl, methylsulfonyl, carboxamide, pyridinylmethyl, and oxo;
heterocyclylcarbonyl; and
ureido.
37. The PCSK9 inhibitor of claim 31 , wherein R 1 is selected from: C 1 -C 4 acyl, arylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, and heteroarylcarbonyl; each optionally substituted with one or two substituents each independently selected from:
C 1 -C 4 alkyl selected from: methyl and t-butyl;
amino;
phenyl, optionally substituted with one or two substituents each independently selected from: methoxy, amino, fluoro, chloro, and hydroxy;
phenylmethyl;
benzoyl, optionally substituted with one substituent selected from: methyl and methylsulfonyl;
phenoxy, optionally substituted with one or two substituents each independently selected from: acetyl, methoxy, methyl, ethyl, bromo, and hydroxymethyl;
carboxyamino, optionally substituted with one substituent selected from: phenylmethyl;
cyclohexyl;
heteroaryl selected from: imidazolyl, indolyl, pyrazolyl, pyridinyl, and triazolyl, each optionally substituted with one or two substituents each independently selected from: methyl and amino;
heterocyclyl selected from: morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyrimidinyl, thiomorpholinyl, each optionally substituted with one or two substituents each independently selected from: methyl, methylsulfonyl, carboxamide, pyridinylmethyl, and oxo;
morpholinylcarbonyl; and
ureido.
38. The PCSK9 inhibitor of claim 31 , wherein R 1 is selected from: acetyl, n-propionyl, n-butanoyl, isovaleryl, valeryl, benzoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclohexylcarbonyl, indolylcarbonyl, pyrazolylcarbonyl, and pyridinylcarbonyl; each optionally substituted with one or two substituents each independently selected from:
C 1 -C 4 alkyl selected from: methyl and t-butyl;
amino;
phenyl, optionally substituted with one or two substituents each independently selected from: methoxy, amino, fluoro, chloro, and hydroxy;
phenylmethyl;
benzoyl, optionally substituted with one substituent selected from: methyl and methylsulfonyl;
phenoxy, optionally substituted with one or two substituents each independently selected from: acetyl, methoxy, methyl, ethyl, bromo, and hydroxymethyl;
carboxyamino, optionally substituted with one substituent selected from: phenylmethyl;
cyclohexyl;
heteroaryl selected from: imidazolyl, indolyl, pyrazolyl, pyridinyl, and triazolyl, each optionally substituted with one or two substituents each independently selected from: methyl and amino;
heterocyclyl selected from: morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyrimidinyl, thiomorpholinyl, each optionally substituted with one or two substituents each independently selected from: methyl, methylsulfonyl, carboxamide, pyridinylmethyl, and oxo;
morpholinylcarbonyl; and
ureido.
39. The PCSK9 inhibitor of claim 31 , wherein R 1 is selected from: acetyl, n-butanoyl, dioxidothiomorpholino)propanoyl, 2-(1-methyl-1H-pyrazol-4-yl)cyclopropane-1-carbonyl, 3-(2-oxopyrrolidin-1-yl)propanoyl, 1-(1-methylpyrrolidin-3-yl)-1H-pyrazole-4-carbonyl, 2-(1-(pyridin-2-ylmethyl)piperidin-4-yl)acetyl, 3-(4-carbamoylpiperazin-1-yl)propanoyl, 3-(1H-imidazol-4-yl)propanoyl, 2-(1-(methylsulfonyl)piperidin-4-yl)acetyl, 6-morpholinonicotinoyl, 3-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl, 3-morpholinopropanoyl, 3-(pyridin-3-yl)propanoyl, 2-(1,1-dioxidotetrahydrothiophen-3-yl)acetyl, 3-(4-methylpiperazin-1-yl)propanoyl, 3-ureidopropanoyl, 3-(1H-1,2,4-triazol-1-yl)propanoyl, 2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetyl, 3-benzylcyclobutane-1-carbonyl, [1,1′-biphenyl]-4-carbonyl, 5-phenylpentanoyl, 4-phenylcyclohexane-1-carbonyl, 5,5-dimethylhexanoyl, 3,5,5-trimethylhexanoyl, 5-(pyridin-4-yl)-1H-pyrazole-3-carbonyl, 3-cyclohexylpropanoyl, 3-(4-aminophenyl)propanoyl, 4-morpholinobutanoyl, 4-(4-(methylsulfonyl)phenyl)-4-oxobutanoyl, 3-(3-aminophenyl)propanoyl, 4-oxo-4-(p-tolyl)butanoyl, 3-(4-methoxyphenyl)propanoyl, 4-morpholino-4-oxobutanoyl, 3-(3-hydroxyphenyl)propanoyl, 4-(((benzyloxy)carbonyl)amino)butanoyl, 3-(4-hydroxyphenyl)propanoyl, 3-(6-aminopyridin-3-yl)propanoyl, 4-(4-bromophenoxy)butanoyl, 4-(4-acetylphenoxy)butanoyl, 3-(pyridin-4-yl)-1H-pyrazole-5-carbonyl, 3-(1H-indol-3-yl)propanoyl, 4-(1H-indol-3-yl)butanoyl, 4-(4-fluorophenyl)butanoyl, 3-(4-fluorophenyl)propanoyl, 3-(4-chlorophenyl)propanoyl, 3-(3-methoxyphenyl)propanoyl, 3-(4-methoxyphenoxy)propanoyl, 4-(4-(hydroxymethyl)-3-methoxyphenoxy)butanoyl, 3-(4-acetylphenoxy)propanoyl, 4-(p-tolyloxy)butanoyl, 4-phenoxybutanoyl, 4-(4-ethylphenoxy)butanoyl, 3-(p-tolyloxy)propanoyl, 4-phenylbutanoyl, 3-(4-hydroxy-3-methoxyphenyl)propanoyl, 4-(4-hydroxyphenyl)butanoyl, 2-(pyridin-3-yl)cyclopropane-1-carbonyl, 1H-indole-6-carbonyl, 2-amino-3-(4-hydroxyphenyl)propanoyl, and 3-(3,4-dihydroxyphenyl)propanoyl.
40. The PCSK9 inhibitor claim 31 , wherein X 1 is an amino acid sequence selected from: TVFTSWEEYLDWV (SEQ ID NO: 3), TVFTS(W6fl)EEYLDWV (SEQ ID NO: 30), and TAFTSWEEYLDWV (SEQ ID NO: 4).
41. The PCSK9 inhibitor of claim 40 , wherein X 1 is the amino acid sequence TVFTSWEEYLDWV (SEQ ID NO: 3).
42. The PCSK9 inhibitor of claim 40 , wherein X 1 is the amino acid sequence TVFTS(W6fl)EEYLDWV (SEQ ID NO: 30).
43. The PCSK9 inhibitor of claim 40 , wherein X 1 is the amino acid sequence TAFTSWEEYLDWV (SEQ ID NO: 4).
44. The PCSK9 inhibitor of claim 31 , wherein X 1 is absent.
45. The PCSK9 inhibitor of claim 31 , wherein X 2 is an amino acid sequence comprising 1 to 4 amino acid residues selected from: glycine and serine.
46. The PCSK9 inhibitor of claim 45 , wherein X 2 is an amino acid sequence selected from: G, GG, SG, GSG, GGSG (SEQ ID NO: 11), GSGG (SEQ ID NO: 12), and SGSG (SEQ ID NO: 13).
47. The PCSK9 inhibitor of claim 31 , wherein X 2 is an amino acid residue selected from: 5-aminopentanoic acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminonoanoic acid, 10-aminodecanoic acid, and 11-aminoundecanoic acid.
48. The PCSK9 inhibitor of claim 47 , wherein X 2 is the amino acid residue 6-aminohexanoic acid.
49. The PCSK9 inhibitor of claim 47 , wherein X 2 is the amino acid residue 7-aminoheptanoic acid.
50. The PCSK9 inhibitor of claim 47 , wherein X 2 is the amino acid residue 8-aminooctanoic acid.
51. The PCSK9 inhibitor of claim 31 , wherein X 2 is absent.
52. The PCSK9 inhibitor of claim 31 , wherein X 3 is an amino acid sequence selected from: P, MP, LMP, ALMP (SEQ ID NO: 14), CALP (SEQ ID NO: 15), CFI(Hyp) (SEQ ID NO: 155), CFIP (SEQ ID NO: 16), CFLP (SEQ ID NO: 17), CRAP (SEQ ID NO: 18), CRL(Hyp) (SEQ ID NO: 19), CRLP (SEQ ID NO: 20), DAMP (SEQ ID NO: 21), DLAP (SEQ ID NO: 22), DLMP (SEQ ID NO: 23), DSYPG (SEQ ID NO: 156), ESFPG (SEQ ID NO: 157), ESYPG (SEQ ID NO: 158), MDSFPG (SEQ ID NO: 159), MESFPG (SEQ ID NO: 160), and SFAFPG (SEQ ID NO: 161).
53. The PCSK9 inhibitor of claim 31 , wherein X 4 is the amino acid residue alanine.
54. The PCSK9 inhibitor of claim 31 , wherein X 4 is the amino acid residue 2,3-diaminopropionic acid.
55. The PCSK9 inhibitor of claim 31 , wherein X 4 is the amino acid residue glutamine.
56. The PCSK9 inhibitor of claim 31 , wherein X 4 is the amino acid residue glycine.
57. The PCSK9 inhibitor of claim 31 , wherein X 4 is the amino acid residue lysine.
58. The PCSK9 inhibitor of claim 31 , wherein X 4 is the amino acid residue valine.
59. The PCSK9 inhibitor of claim 31 , wherein X 5 is the amino acid residue arginine.
60. The PCSK9 inhibitor of claim 31 , wherein X 5 is the amino acid residue homo-arginine.
61. The PCSK9 inhibitor of claim 31 , wherein X 6 is an amino acid sequence selected from: L, S, LL, LAR, LDR, LER, LGC, LGR, LLA, LLC, LLQ, LLR, LPC, LPR, LSR, LTR, SQGC (SEQ ID NO: 24), SQCEY (SEQ ID NO: 25), SQCWF (SEQ ID NO: 26), and SQGCW (SEQ ID NO: 27).
62. The PCSK9 inhibitor of claim 31 , wherein X 6 is absent.
63. The PCSK9 inhibitor of claim 31 , wherein X 7 is tryptophan.
64. The PCSK9 inhibitor of claim 31 , wherein X 7 is 6-fluorotryptophan.
65. The PCSK9 inhibitor of claim 31 , wherein X 7 is 6-chlorotryptophan.
66. The PCSK9 inhibitor of claim 31 , wherein X 7 is 6-bromotryptophan.
67. The PCSK9 inhibitor of claim 31 , wherein X 7 is 6-methyltryptophan.
68. The PCSK9 inhibitor of claim 31 , wherein R 2 is amino.
69. The PCSK9 inhibitor of claim 31 , wherein R 2 is absent.
70. The PCSK9 inhibitor of claim 31 , selected from the following compounds and pharmaceutically acceptable salts thereof:
(SEQ ID NO: 29)
Ac-TVFTSWEEYLDWV-GSG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 38)
Ac-TVFTSWEEYLDWV-GSG-CWNLGRIGSQGC-NH2;
(SEQ ID NO: 40)
Ac-TVFTSWEEYLDWV-GGSG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 41)
Ac-TVFTSWEEYLDWV-GSGG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 42)
Ac-TVFTSWEEYLDWV-(Aoc)-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 44)
Ac-TVFTSWEEYLDWV-(Ahx)-CWNLKRIGSQGC-NH2
(SEQ ID NO: 46)
Ac-TVFTSWEEYLDWV-GSG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 47)
Ac-TVFTSWEEYLDWV-GSG-DLMPWNLVRIGLLR-NH2;
(SEQ ID NO: 48)
Ac-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 49)
Ac-GSG-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 51)
Ac-TVFTSWEEYLDWV-(Ahp)-CWNLKRIGSQGC-NH2;
(SEQ ID NO: 149)
Ac-TVFTSWEEYLDWV-SGG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 52)
Ac-TVFTSWEEYLDWV-GSGG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 53)
SG-CFIPWNLQRIGLLC-NH2;
(SEQ ID NO: 54)
SG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 55)
SG-DLMPWNLVRIGLLR;
(SEQ ID NO: 56)
Ac-SG-CFIPWNLQRIGLLC-NH2;
(SEQ ID NO: 57)
Ac-SG-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 58)
Ac-CFIPWNLQRIGLLC-NH2;
(SEQ ID NO: 59)
Ac-CRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 62)
Ac-DLMPWNLVRIGLLR-NH2;
(SEQ ID NO: 64)
Ac-SG-CRL(Hyp)WNLQRIGLPC-NH2;
(SEQ ID NO: 65)
Ac-TVFTSWEEYLDWV-GSGG-CFLPWNLQRIGLLC-NH2;
(SEQ ID NO: 66)
Ac-CWNLKRIGSQGCW-NH2;
(SEQ ID NO: 67)
Ac-GSG-CWNLKRIGSQGCW-NH2;
(SEQ ID NO: 69)
Ac-DLMAWNLVRIGLLR-NH2;
(SEQ ID NO: 70)
Ac-DLAPWNLVRIGLLR-NH2;
(SEQ ID NO: 71)
Ac-DAMPWNLVRIGLLR-NH2;
(SEQ ID NO: 72)
Ac-ALMPWNLVRIGLLR-NH2;
(SEQ ID NO: 73)
Ac-DLMPWNLVRIGLL-NH2;
(SEQ ID NO: 74)
Ac-DLMPWNLVRIGL-NH2;
(SEQ ID NO: 75)
Ac-DLMPWNLVRIG-NH2;
(SEQ ID NO: 77)
Ac-LMPWNLVRIGLLR-NH2;
(SEQ ID NO: 78)
Ac-MPWNLVRIGLLR-NH2;
(SEQ ID NO: 79)
Ac-PWNLVRIGLLR-NH2;
(SEQ ID NO: 81)
Ac-DLMPWNLVRIGLLA-NH2;
(SEQ ID NO: 82)
Ac-DLMPWNLVRIGLAR-NH2;
(SEQ ID NO: 83)
Ac-DLMPWNLVRIGALR-NH2;
(SEQ ID NO: 87)
Ac-DLMPWNLARIGLLR-NH2;
(SEQ ID NO: 150)
GCLWNLKRIGSQCWF;
(SEQ ID NO: 94)
Ac-CRLPWNLKRIGLPC-NH2;
(SEQ ID NO: 95)
Ac-CRLPWNLQRIGLAC-NH2;
(SEQ ID NO: 96)
Ac-CRLPWNLQRIGAPC-NH2;
(SEQ ID NO: 100)
Ac-CRLPWNLARIGLPC-NH2;
(SEQ ID NO: 101)
Ac-CRLAWNLQRIGLPC-NH2;
(SEQ ID NO: 102)
Ac-CRAPWNLQRIGLPC-NH2;
(SEQ ID NO: 103)
Ac-CALPWNLQRIGLPC-NH2;
(SEQ ID NO: 107)
Ac-CRLPWNLQRIGLGC-NH2;
(SEQ ID NO: 108)
Ac-CRLPWNLQRIGGGC-NH2;
(SEQ ID NO: 109)
Ac-CRL(Ach)WNLQRIGLPC-NH2;
(SEQ ID NO: 114)
Ac-GCLWNLKRIGSQCWF-NH2;
(SEQ ID NO: 151)
Ac-GCLWNLARIGSQCWF-NH2;
(SEQ ID NO: 115)
Ac-FCLWNLARIGSQCWF-NH2;
(SEQ ID NO: 152)
GCLWNLKRIGSQCWF-NH2;
(SEQ ID NO: 116)
WCLWNLKRIGSQCWF-NH2;
(SEQ ID NO: 153)
Ac-GCLWNLKRIGSQCWF;
(SEQ ID NO: 117)
Ac-WCLWNLKRIGSQCWF;
(SEQ ID NO: 118)
Ac-TVFTSWEEYLDWV-(Ahx)-AWNLKRIGS-NH2;
(SEQ ID NO: 119)
Ac-TVFTSWEEYLDWV-(Ahx)-AWNLKRIG-NH2;
(SEQ ID NO: 123)
Ac-FCLWNLKRIGAQCWF-NH2;
(SEQ ID NO: 124)
Ac-GSG-CWNL(Dpr)RIGSQGC-NH2;
(SEQ ID NO: 126)
Ac-CRLPWNLQRIGLpC-NH2;
(SEQ ID NO: 127)
Ac-CRLPWNLQRIGIPC-NH2;
(SEQ ID NO: 128)
Ac-CRLPWNLQRiGLPC-NH2;
(SEQ ID NO: 129)
Ac-CRLPWNLQrIGLPC-NH2;
(SEQ ID NO: 130)
Ac-CRLPWNLqRIGLPC-NH2;
(SEQ ID NO: 131)
Ac-CRLPWNIQRIGLPC-NH2;
(SEQ ID NO: 132)
Ac-CRLPWnLQRIGLPC-NH2;
(SEQ ID NO: 133)
Ac-CRLPRwNLQRIGLPC-NH2;
(SEQ ID NO: 134)
Ac-CRLpWNLQRIGLPC-NH2;
(SEQ ID NO: 135)
Ac-CRlPWNLQRIGLPC-NH2;
(SEQ ID NO: 136)
Ac-CrLPWNLQRIGLPC-NH2;
(SEQ ID NO: 137)
Ac-cRLPWNLQRIGLPC-NH2;
(SEQ ID NO: 144)
Ac-CRLPWNLQ(homoR)IGLPC-NH2;
(SEQ ID NO: 146)
Ac-PWNLVRIGL-NH2;
(SEQ ID NO: 162)
Ac-SG-DLMPWNLVRIGLLR-NH2;
(SEQ ID NO: 163)
n-PrC(O)-WNLVRIGLLR-NH2;
(SEQ ID NO: 164)
Ac-G-LMPWNLVRIGLLR-NH2;
(SEQ ID NO: 165)
Ac-GG-MPWNLVRIGLLR-NH2;
(SEQ ID NO: 193)
Ac-MDSFPGWNLVRIGLLR-NH2;
(SEQ ID NO: 194)
Ac-SFAFPGWNLVRIGLLR-NH2;
(SEQ ID NO: 195)
Ac-DSYPGWNLVRIGLLR-NH2;
(SEQ ID NO: 196)
Ac-ESYPGWNLVRIGLLR-NH2;
(SEQ ID NO: 197)
Ac-ESFPGWNLVRIGLLR-NH2;
(SEQ ID NO: 198)
Ac-DLMPWNLKRIGLLR-NH2;
(SEQ ID NO: 200)
Ac-DLMPWNLVRIGLPR-NH2;
(SEQ ID NO: 267)
Ac-ESFPGWNLV(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 268)
Ac-SFAFPGWNLV(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 269)
Ac-MESFPGWNLV(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 270)
Ac-DSYPGWNLV(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 271)
Ac-ESYPGWNLV(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 272)
Ac-SFAFPGWNLK(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 273)
Ac-MESFPGWNLK(homoR)IGLLR-NH 2 ;
(SEQ ID NO: 281)
Ac-TVFTS(W6fl)EEYLDWV-GSG-CRLPWNLQRIGLPC-NH2;
and
(SEQ ID NO: 282)
Ac-SG-CFI(Hyp)WNLQRIGLLC-NH2.
71. An inhibited PCSK9 comprising a PCSK9 inhibitor of claim 1 bound to PCSK9.
72. A pharmaceutical composition comprising a PCSK9 inhibitor of claim 1 and a pharmaceutically acceptable carrier.
73. A PCSK9 inhibitor, or pharmaceutically acceptable salts thereof selected from the group consisting of: