Cyclic polypeptides for PCSK9 inhibition
Inventors
Ricardo, Alonso • Tucker, Thomas Joseph • Boyer, Nicolas Cedric • Dhamnaskar, Ketki Ashok • Ma, Zhong • Kerekes, Angela Dawn • Wu, Chengwei • Ha, Sookhee Nicole • Youm, Hyewon • Bianchi, Elisabetta • Branca, Danila • Ingenito, Raffaele • Costantini, Willy • Shahripour, Aurash • Xiong, Yusheng
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11505575-B2
Publication Date
2022-11-22
Expiration Date
Abstract
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.
Core Innovation
The invention relates to cyclic peptide compounds having structures of Formula (I), Formula (II), and Formula (III), and pharmaceutically acceptable salts thereof. The cyclic peptide structures are defined by protected amino acid side chains or acyl protected amines, with specified residue-position constraints, optional N-methylation, and R or S configuration possibilities for each amino acid residue.
The invention is directed to inhibition of PCSK9 activity and inhibition of the interaction between human PCSK9 and the EGF-A domain of human LDLR. It includes pharmaceutical compositions comprising the disclosed cyclic peptides and describes therapeutic use for reducing LDL cholesterol. The background description states that PCSK9 binds to LDLR, promotes LDLR degradation, and that inhibition increases LDLR surface levels and lowers blood LDL.
The invention also provides treatment methods for hypercholesterolemia and hypercholesterolemia with comorbid disease. The comorbid diseases include nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, and high blood pressure. The disclosed assays and reagents include TR-FRET and fluorescence-based FRET formats, and LCMS confirmation is referenced for constructed assay reagents.
Claims Coverage
The independent claims cover cyclic peptides defined by Formula (I), Formula (II), Formula (III), and a separate independent selection set of labeled cyclic peptide embodiments. Across these independent claims, the inventive features include specific structure constraints for substituent selections, optional N-methylation and stereochemical R/S configuration, pharmaceutically acceptable salts, and covalent binding by a linking moiety in Formula (III).
Cyclic peptide of Formula (I)
A cyclic peptide having the structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A1 is an acyl or sulfonyl protected amino acid side chain or an acyl protected amine; R4, R5, R6, R7, R8, and R10 are selected from specified amino acid side-chain groups; P1 is H, methyl, or an acetyl group; X is H or F; n is 0 or 1; p is 2, 3, or 4; each amino acid residue is optionally N-methylated; and each amino acid residue can be in the R or S configuration.
Cyclic peptide of Formula (II)
A cyclic peptide having the structure of Formula (II), or a pharmaceutically acceptable salt thereof, wherein A1 is an acyl or sulfonyl protected amino acid selected from specified amino acid side-chain options or an acyl protected amine; R4 is the amino acid side chain of THR; R5, R6, R7, R8, R9, and R10 are selected from specified amino acid side-chain groups; P1 is H, methyl, or an acetyl group; n is 0 or 1; p is 2, 3, 4, 5, or 6; each amino acid residue is optionally N-methylated; and each amino acid residue can be in the R or S configuration.
Cyclic peptide of Formula (III)
A cyclic peptide having the structure of Formula (III), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from PRO and HIS side chains; R6 is selected from specified amino acid side-chain groups; R7 is selected from ALA and GLU side chains or is covalently bound to R3 by a linking moiety; R9 is selected from specified amino acid side chains; R10 is the amino acid side chain of THR; each amino acid residue is optionally N-methylated; each amino acid residue can be in the R or S configuration; and either R3 and R7 or R6 and R10 are covalently bound by a linking moiety selected from the group.
Cyclic peptide selected from a labeled set
A cyclic peptide selected from a list of labeled cyclic peptides including 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, and 100.
Overall, the independent claims primarily define cyclic peptides through Formula (I), Formula (II), or Formula (III) structural constraints, including protected side-chain selections, optional N-methylation, R/S stereochemistry, and covalent linking moieties, and additionally provide an independent recitation of cyclic peptides selected from a labeled set of embodiments.
Stated Advantages
Inhibition of PCSK9–LDLR interaction.
Inhibition of PCSK9 activity.
Inhibiting PCSK9 increases LDLR surface levels and lowers blood LDL.
Reducing LDL cholesterol.
Treatment of hypercholesterolemia.
Treatment of hypercholesterolemia with comorbid diseases selected from nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, or high blood pressure.
Documented Applications
Methods for inhibiting PCSK9 activity in a subject by administering a therapeutically effective amount of the cyclic peptide.
Methods for inhibiting the interaction between human PCSK9 and the EGF-A domain of human LDLR.
Methods for reducing LDL cholesterol in a subject by administering the cyclic peptide.
Treatment of hypercholesterolemia in a subject by administering a therapeutically effective amount of the cyclic peptide.
Treatment of hypercholesterolemia when the subject has a comorbid disease selected from nephrotic syndrome, kidney failure, coronary artery disease, atherosclerosis, stroke, peripheral vascular disease, diabetes, or high blood pressure.
Interested in licensing this patent?