Cyclic polypeptides for PCSK9 inhibition
Provided herein are cyclic polypeptide compounds that can, e.g., bind specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and optionally also inhibit interaction between human PCSK9 and human low density lipoprotein receptor (LDLR), and pharmaceutical compositions comprising one or more of these compounds. Also provided are methods of reducing LDL cholesterol level in a subject in need thereof that include administering to the subject one or more of the cyclic polypeptide compounds or a pharmaceutical composition provided herein.
1. A cyclic peptide having the structure of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
A 1 is an acyl or sulfonyl protected amino acid side chain of
or is an acyl protected amine;
R 4 is selected from the group consisting of the amino acid side chains of THR,
R 5 is the amino acid side chain of
R 6 is selected from the group consisting of the amino acid side chains of
R 7 is selected from the group consisting of the amino acid side chains of GLU and ALA;
R 8 is selected from the group consisting of the amino acid side chains of TYR and
R 10 is selected from the group consisting of the amino acid side chains of THR,
SER, and LYS;
P 1 is H, methyl, an acetyl group, or
X is H or F;
n is 0 or 1;
p is 2, 3, or 4;
wherein each amino acid residue is optionally an N-methylated amino acid; and
wherein each amino acid residue can be in the R or S configuration.
2. The cyclic peptide of claim 1 , wherein the cyclic peptide is selected from:
014
015
016
017
018
019
020
023
024
025
026
027
028
029
030
031
033
034
035
036
037
038
039
.
3. The cyclic peptide of claim 1 , wherein the cyclic peptide is selected from:
014
015
016
017
018
023
033
034
035
036
037
.
4. A cyclic peptide having the structure of Formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
A 1 is an acyl or sulfonyl protected amino acid selected from the group consisting of the amino acid side chains of
or is an acyl protected amine;
R 4 is the amino acid side chain of THR;
R 5 is selected from the group consisting of the amino acid side chains of
R 6 is selected from the group consisting of the amino acid side chains of
R 7 is selected from the group consisting of the amino acid side chains of GLU and
R 8 is selected from the group consisting of the amino acid side chains of TYR and
R 9 is selected from the group consisting of the amino acid side chains of
R 10 is selected from the group consisting of the amino acid side chains of THR,
P 1 is H, methyl, an acetyl group, or
n is 0 or 1;
p is 2, 3, 4, 5, or 6;
wherein each amino acid residue is optionally an N-methylated amino acid; and
wherein each amino acid residue can be in the R or S configuration.
5. The cyclic peptide of claim 4 , wherein the cyclic peptide is selected from:
043
044
070
071
072
073
074
075
078
079
080
081
083
084
085
088
089
096
098
099
6. The cyclic peptide of claim 4 , wherein the cyclic peptide is selected from:
043
044
074
079
099
7. A cyclic peptide having the structure of Formula (III):
or a pharmaceutically acceptable salt thereof;
wherein:
R 3 is selected from the group consisting of the amino acid side chains of PRO and HIS;
R 6 is selected from the group consisting of the amino acid side chains of
R 7 is selected from the group consisting of the amino acid side chains of ALA and GLU or is covalently bound to R 3 by a linking moiety;
R 9 is selected from the group consisting of the amino acid side chains of
R 10 is the amino acid side chain of THR;
wherein each amino acid residue is optionally an N-methylated amino acid;
wherein each amino acid residue can be in the R or S configuration; and
provided either R 3 and R 7 , or R 6 and R 10 are covalently bound by a linking moiety selected from the group consisting of
8. The cyclic peptide of claim 7 , wherein the cyclic peptide is selected from:
101
106
107
108
109
110
111
112
114
115
118
119
120
9. The cyclic peptide of claim 8 , wherein the cyclic peptide is selected from:
107
110
10. A cyclic peptide selected from:
001
002
003
004
005
006
007
008
009
010
011
012
013
021
022
032
040
041
042
046
047
048
050
053
056
057
058
059
060
061
062
063
064
065
066
067
068
069
076
077
082
086
087
090
091
092
093
094
095
097
100
11. The cyclic peptide of claim 10 , wherein the cyclic peptide is selected from:
002
003
032
040
042
048
077
093
12. A pharmaceutical composition comprising the cyclic peptide of claim 1 and a pharmaceutically acceptable carrier.
13. A method of reducing low density lipoprotein (LDL) cholesterol level in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the cyclic peptide of claim 1 .
14. The method of claim 13 , wherein the subject has hypercholesterolemia.
15. The method of claim 14 , wherein the cyclic peptide inhibits the interaction between human PCSK9 and epidermal growth factor-like repeat A (EGF-A) domain of human low density lipoprotein (LDLR).
16. A method of treating hypercholesterolemia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the cyclic peptide of claim 1 .
17. The method of claim 16 , wherein the subject further suffers from a disease that shows comorbidity with hypercholesterolemia.
18. The method of claim 17 , wherein the disease that shows comorbidity with hypercholesterolemia is selected from the group consisting of nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure.
19. A method of inhibiting PCSK9 activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the cyclic peptide of claim 1 .
20. A method of inhibiting PCSK9 activity in a cell comprising contacting the cell with the cyclic peptide of claim 1 .
21. A method of inhibiting the interaction between PCSK9 and the EGF-A domain of LDLR in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the cyclic peptide of claim 1 .
22. The method of claim 13 , wherein the administration is selected from the group consisting of oral, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, and intravitreal.
23. The cyclic peptide of claim 1 , wherein the cyclic peptide is