7S5H

PCSK9(deltaCRD) in complex with cyclic peptide 35

7S5H の概要

• エントリーDOI: 10.2210/pdb7s5h/pdb
• 分子名称: Pro-peptide from Proprotein convertase subtilisin/kexin type 9, Proprotein convertase subtilisin/kexin type 9, Z50-DNP-DAL-PHE-FTR-PRO-THR-0A1-3WX, ... (5 entities in total)
• 機能のキーワード: cholesterol, ldl receptor, egfa domain, protein binding, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 48079.09

構造登録者

Orth, P. (登録日: 2021-09-10, 公開日: 2021-11-03, 最終更新日: 2024-04-24)

主引用文献

Tucker, T.J.,Embrey, M.W.,Alleyne, C.,Amin, R.P.,Bass, A.,Bhatt, B.,Bianchi, E.,Branca, D.,Bueters, T.,Buist, N.,Ha, S.N.,Hafey, M.,He, H.,Higgins, J.,Johns, D.G.,Kerekes, A.D.,Koeplinger, K.A.,Kuethe, J.T.,Li, N.,Murphy, B.,Orth, P.,Salowe, S.,Shahripour, A.,Tracy, R.,Wang, W.,Wu, C.,Xiong, Y.,Zokian, H.J.,Wood, H.B.,Walji, A.
A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.
J.Med.Chem., 64:16770-16800, 2021

PubMed Abstract: Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as , we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.

PubMed: 34704436
DOI: 10.1021/acs.jmedchem.1c01599

実験手法

X-RAY DIFFRACTION (1.272 Å)