1. Identification of a PCSK9-LDLR disruptor peptide with in vivo function
- Author
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Katsumasa Nakajima, David Nettleton, Guoming Zhu, Debra Burdick, Alexander W. Koch, Qing Yang, Glen Spraggon, Margaret E. Brousseau, Guanjing Chen, Lisa Ames, Raphael Gattlen, Flyer Alec, Jennifer Poirier, Jingzhou Li, Mohindra Seepersaud, Dawn Kelly-Sullivan, Stephanie Pickett, Xavier Pelle, Lauren Perry, Raj Chopra, Jakal Amin, Jerome Andre, Danuta Lubicka, Victoria Vera, Philipp Grosche, Patel Tajesh Jayprakash, Ian Lewis, Lihua Yang, Eugene Liu, Andrei Golosov, jinghua yu, Li Fan, Patrick C. Reid, Lauren G. Monovich, Shari L. Caplan, Meihui Pan, Diana Dubiel, Vanitha Subramanian, Kevin B. Clairmont, Johannes Ottl, Mei Xu, and Andreas Marzinzik
- Subjects
Male ,Protein Conformation ,Clinical Biochemistry ,Allosteric regulation ,Peptide ,Biology ,Ligands ,Biochemistry ,Mice ,Drug Discovery ,Animals ,Humans ,Molecular Biology ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,PCSK9 ,Subtilisin ,Hep G2 Cells ,Proprotein convertase ,Small molecule ,Cell biology ,Mice, Inbred C57BL ,Receptors, LDL ,chemistry ,LDL receptor ,Molecular Medicine ,Kexin ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,Peptides - 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 1013 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., 13PCSK9i). In mice, 13PCSK9i reduces plasma cholesterol levels and increases hepatic LDLR density in a dose-dependent manner. 13PCSK9i functions by a unique, allosteric mechanism and is the smallest molecule identified to date with in vivo PCSK9-LDLR disruptor function.
- Published
- 2022
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