Identification of a PCSK9-LDLR disruptor peptide with in vivo function

被引：35

作者：

Brousseau, Margaret E. ^{[1
]}

Clairmont, Kevin B. ^{[1
]}

Spraggon, Glen ^{[2
]}

Flyer, Alec N. ^{[1
]}

Golosov, Andrei A. ^{[1
]}

Grosche, Philipp ^{[3
]}

Amin, Jakal ^{[1
]}

Andre, Jerome ^{[3
]}

Burdick, Debra ^{[1
]}

Caplan, Shari ^{[1
]}

Chen, Guanjing ^{[1
]}

Chopra, Raj ^{[1
]}

Ames, Lisa ^{[1
]}

Dubiel, Diana ^{[1
]}

Fan, Li ^{[1
]}

Gattlen, Raphael ^{[3
]}

Kelly-Sullivan, Dawn ^{[1
]}

Koch, Alexander W. ^{[1
]}

Lewis, Ian ^{[3
]}

Li, Jingzhou ^{[1
]}

Liu, Eugene ^{[1
]}

Lubicka, Danuta ^{[1
]}

Marzinzik, Andreas ^{[3
]}

Nakajima, Katsumasa ^{[1
]}

Nettleton, David ^{[1
]}

Ottl, Johannes ^{[3
]}

Pan, Meihui ^{[1
]}

Patel, Tajesh ^{[1
]}

Perry, Lauren ^{[1
]}

Pickett, Stephanie ^{[3
]}

Poirier, Jennifer ^{[1
]}

Reid, Patrick C. ^{[4
]}

Pelle, Xavier ^{[3
]}

Seepersaud, Mohindra ^{[1
]}

Subramanian, Vanitha ^{[1
]}

Vera, Victoria ^{[1
]}

Xu, Mei ^{[1
]}

Yang, Lihua ^{[1
]}

Yang, Qing ^{[1
]}

Yu, Jinghua ^{[1
]}

Zhu, Guoming ^{[1
]}

Monovich, Lauren G. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, 22 Windsor St & 181 Massachusetts Ave, Cambridge, MA 02139 USA

[2] Novartis Res Fdn, Genom Inst, 10675 John Jay Hopkins Dr, San Diego, CA 92121 USA

[3] Novartis Inst BioMed Res, Fabrikstr 2,Novartis Campus, CH-4056 Basel, Switzerland

[4] PeptiDream Inc, Meguro Ku, KOL Bldg,Room 405,4-6-1 Komaba, Tokyo 1538904, Japan

来源：

CELL CHEMICAL BIOLOGY | 2022年 / 29卷 / 02期

关键词：

SMALL-MOLECULE INHIBITORS; FACTOR-LIKE REPEAT; CRYSTAL-STRUCTURE; ANNEXIN A2; PROTEIN; DESIGN; BINDING; ANTIBODIES; DISPLAY; SITE;

D O I：

10.1016/j.chembiol.2021.08.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors. We employ an affinity-based screen of 10(13) in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands that utilize a unique, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction. Structure-based design led to molecules with enhanced function and pharmacokinetic properties (e.g., (13)PCSK9i). In mice,(13)PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. (13)PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.

引用

页码：249 / +

页数：16

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