Abstract 10516: Identification of a PCSK9-LDLR Disruptor Macrocycle with in vivo Function

• DOI: 10.1161/circ.144.suppl_1.10516
• Publication Date: 2022-03-19T23:58:21Z
• Authors: Margaret E Brousseau; Kevin B Clairmont; Glen Spraggon; Alec N Flyer; Andrei A Golosov; Philipp Grosche; Jérôme André; Shari Caplan; Guanjing Chen; Li Fan; Raphael Gattlen; Alexander Koch; Ian Lewis; Jingzhou Li; Eugene Liu; Danuta Lubicka; Andreas Marzinzik; Katsumasa Nakajima; David Nettleton; Johannes Ottl; Meihui Pan; Tajesh Patel; Stephanie Pickett; Jennifer Poirier; Patrick C Reid; Xavier Pelle; Vanitha Subramanian; Victoria Vera; Mei Xu; Lihua Yang; Qing Yang; jinghua yu; Guoming Zhu; Lauren G Monovich
• Keywords: PCSK9; Identification

Elevated LDL-C is a major risk factor for atherosclerotic cardiovascular disease, the leading cause of death worldwide. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has pronounced effects on levels via its modulation hepatic LDL receptors (LDLR), main pathway cholesterol removal from circulation. The epidermal growth precursor homology domain A (EGF-A) LDLR serves as primary contact with PCSK9 flat interface, presenting challenge identifying small molecule PCSK9-LDLR disruptors. We employed an affinity-based screen 10 13 in vitro -translated macrocyclic peptides to identify high affinity ligands that utilize novel, induced-fit pocket and partially disrupt interaction (Hit 1 - FRET, IC 50 2 nM, max 41%). Structure-based design led PCSK9i , enhanced function (PCSK9-LDLR 78%) pharmacokinetic properties suitable vivo evaluation. To determine if ’s functional activity would translate C57BL/6 mice were dosed vehicle or subcutaneous injection twice-daily 3 days, blood liver collected measurement plasma total (TC) density. antibody was included positive control. As illustrated figure, increased density dose-dependent manner. Despite being 1/100 th size, (MW = 1.65 kDa) par 144 kDa). Plasma TC significantly reduced versus all dose groups, similar reductions noted 30 mg/kg groups (44% 48%, respectively). In summary, breaks new ground previously undescribed allosteric mechanism and, turn, smallest identified date disruptor function.