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 polycyclic peptide of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from the group consisting of F, OH, Br, Me, OMe, CI, and CF 3 ;
A 1 is H, an acyl protected amine,
R 1 is selected from the group consisting of the amino acid side chains of
and TYR;
R 2 is selected from the group consisting of the amino acid side chains of ALA,
THR, and VAL;
R 3 is selected from the group consisting of the amino acid side chains of ALA, ASP,
and PRO;
R 4 is selected from the group consisting of the amino acid side chains of
THR, and VAL;
R 5 is selected from the group consisting of the amino acid side chains of
L 1 is
A 2 is absent or
P 1 is selected from the group consisting of H, acetyl,
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 polycyclic peptide of claim 1 , wherein the polycyclic peptide is selected from:
002
003
004
005
006
007
008
009
010
013
014
016
017
018
019
024
025
026
027
030
032
033
041
042
043
044
048
049
050
051
052
053
054
055
059
060
061
062
063
064
069
070
071
072
073
082
083
084
085
086
087
100
101
103
131
133
135
136
187
217
228
229
230
231
232
233
245
246
247
248
249
250
269
271
272
273
274
275
277
278
279
280
281
283
284
285
286
287
288
289
299
300
308
318
319
323
324
338
344
345
354
355
356
357
358
359
360
361
362
372
373
374
375
376
377
382
383
386
387
388
406
407
408
423
424
425
426
427
439
441
442
443
444
445
446
447
448
452
456
462
463
464
465
466
467
468
473
474
479
481
484
485
490
491
492
3. The polycyclic peptide of claim 1 , wherein the polycyclic peptide is selected from:
004
010
248
275
277
281
358
359
360
362
373
376
377
382
383
386
387
388
406
4. The polycyclic peptide of claim 1 , wherein the polycyclic peptide is:
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a polycyclic 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 polycyclic peptide of claim 1 .
7. The method of claim 6 , wherein the subject has hypercholesterolemia.
8. The method of claim 7 , wherein the polycyclic 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 polycyclic 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 polycyclic peptide of claim 1 .
13. A method of inhibiting PCSK9 activity in a cell comprising contacting the cell with the polycyclic 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 polycyclic 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.