| Autor: |
Brousseau, Margaret E, Clairmont, Kevin B, Spraggon, Glen, Flyer, Alec N, Golosov, Andrei A, Grosche, Philipp, André, Jérôme, Caplan, Shari, Chen, Guanjing, Fan, Li, Gattlen, Raphael, Koch, Alexander, Lewis, Ian, Li, Jingzhou, Liu, Eugene, Lubicka, Danuta, Marzinzik, Andreas, Nakajima, Katsumasa, Nettleton, David, Ottl, Johannes, Pan, Meihui, Patel, Tajesh, Pickett, Stephanie, Poirier, Jennifer, Reid, Patrick C, Pelle, Xavier, Subramanian, Vanitha, Vera, Victoria, Xu, Mei, Yang, Lihua, Yang, Qing, yu, jinghua, Zhu, Guoming, Monovich, Lauren G |
| Zdroj: |
Circulation (Ovid); November 2021, Vol. 144 Issue: Supplement 1 pA10516-A10516, 1p |
| Abstrakt: |
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 LDL-C levels via its modulation of hepatic LDL receptors (LDLR), the main pathway for cholesterol removal from the circulation. 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 employed an affinity-based screen of 1013in vitro-translated macrocyclic peptides to identify high affinity PCSK9 ligands that utilize a novel, induced-fit pocket and partially disrupt the PCSK9-LDLR interaction (Hit 1 - PCSK9-LDLR FRET, IC502 nM, Amax41%). Structure-based design led to 13PCSK9i, a molecule with enhanced in vitrofunction (PCSK9-LDLR FRET, IC502 nM, Amax78%) and pharmacokinetic properties suitable for in vivoevaluation. To determine if 13PCSK9i’s functional activity in vitrowould translate in vivo, C57BL/6 mice were dosed with vehicle or 13PCSK9iviasubcutaneous injection twice-daily for 3 days, and blood and liver were collected for the measurement of plasma total cholesterol (TC) and hepatic LDLR density. A PCSK9 antibody was included as a positive control. As illustrated in the figure, 13PCSK9iincreased hepatic LDLR density in a dose-dependent manner. Despite being 1/100thits size, 13PCSK9i(MW = 1.65 kDa) increased hepatic LDLR density on par with a PCSK9 antibody (MW = 144 kDa). Plasma TC levels were significantly reduced versus vehicle in all 13PCSK9idose groups, with similar reductions noted in the 13PCSK9i30 mg/kg and PCSK9 antibody groups (44% and 48%, respectively). In summary, 13PCSK9ibreaks new ground with its previously undescribed allosteric mechanism and, in turn, as the smallest molecule identified to date with in vivoPCSK9-LDLR disruptor function. |
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