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 of Formula (II):
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from the group consisting of F, OH, Br, Me, OMe, Cl, and CF 3 ;
A 1 is an acyl protected amine or is absent; or A 1 is an amine that is linked by a covalent bond to amino acids selected from the group consisting of (MFF), (MFF-HIS), (MFF-HIS-NVA), and (LYS-SER-NVA), wherein MFF has the amino acid structure
NVA has the amino acid structure
and the terminal amine is acyl protected;
R 1 is selected from the group consisting of the amino acid side chains of
and THR;
R 2 is selected from the group consisting of the amino acid side chains of
ALA, GLY, and
R 3 is selected from the group consisting of the amino acid side chains of ALA, ASP, ASN,
and THR;
R 4 is selected from the group consisting of the amino acid side chains of
ALA, HIS, and THR;
R 5 is selected from the group consisting of the amino acid side chains of
A 2 is absent or
wherein each amino acid residue is optionally an N-methylated amino acid;
wherein each amino acid residue can be the R or S-enantiomer configuration; and
n is 0, 1, 2, 3, or 4.
2. The cyclic peptide of claim 1 , wherein the cyclic peptide is selected from the group consisting of:
011
012
020
021
022
023
031
143
144
145
146
147
148
149
155
156
157
159
162
163
164
165
166
167
168
171
172
173
174
182
188
190
192
193
197
205
214
224
225
226
227
234
235
236
237
238
239
240
241
242
243
264
265
267
268
306
307
309
318
326
340
or a pharmaceutically acceptable salt thereof.
3. The cyclic peptide of claim 1 , wherein the cyclic peptide is selected from the group consisting of:
171
318
or a pharmaceutically acceptable salt thereof.
4. The cyclic peptide of claim 1 , wherein the cyclic peptide is:
318
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising the cyclic peptide of claim 1 and a pharmaceutically acceptable carrier.
6. 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 .
7. The method of claim 6 , wherein the subject has hypercholesterolemia.
8. The method of claim 7 , 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).
9. 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 .
10. The method of claim 9 , wherein the subject further suffers from a disease that shows comorbidity with hypercholesterolemia.
11. The method of claim 10 , 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.
12. 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 .
13. A method of inhibiting PCSK9 activity in a cell comprising contacting the cell with the cyclic peptide of claim 1 .
14. 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 .
15. The method of claim 6 , wherein the administration is selected from the group consisting of oral, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, and intravitreal.