Identification of a PCSK9-LDLR disruptor peptide with in vivo function. Issue 2 (17th February 2022)

• Record Type: Journal Article
• Authors: Brousseau, Margaret E.; Clairmont, Kevin B.; Spraggon, Glen; Flyer, Alec N.; Golosov, Andrei A.; Grosche, Philipp; Amin, Jakal; Andre, Jerome; Burdick, Debra; Caplan, Shari; Chen, Guanjing; Chopra, Raj; Ames, Lisa; Dubiel, Diana; Fan, Li; Gattlen, Raphael; Kelly-Sullivan, Dawn; Koch, Alexander W.; Lewis, Ian; Li, Jingzhou; Liu, Eugene; Lubicka, Danuta; Marzinzik, Andreas; Nakajima, Katsumasa; Nettleton, David; Ottl, Johannes; Pan, Meihui; Patel, Tajesh; Perry, Lauren; Pickett, Stephanie; Poirier, Jennifer; Reid, Patrick C.; Pelle, Xavier; Seepersaud, Mohindra; Subramanian, Vanitha; Vera, Victoria; Xu, Mei; Yang, Lihua; Yang, Qing; Yu, Jinghua; Zhu, Guoming; Monovich, Lauren G.;
• Is Part Of: Cell chemical biology. Volume 29:Issue 2(2022)
• Page Start: 249
• Page End: 258.e5
• Publication Date: 2022-02-17
• Subjects: LDL -- LDL receptor -- macrocycle -- PCSK9 -- structure -- protein-protein interaction disruptor; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2021.08.012
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical abstract: Highlights: Discovery of PCSK9 ligands that utilize a unique, induced-fit pocket A nonbiologic agent capable of disrupting the PCSK9-LDLR interaction in vivo Abstract : Brousseau et al. have identified macrocyclic peptides that bind PCSK9 with low-nanomolar affinity, disrupt PCSK9 function, and utilize an induced-fit pocket. 13 PCSK9i functions by a distinct, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.