A Comparative Assessment Study of Known Small-molecule GPVI Modulators

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Feb 18

PMID 35178172

Authors

Holly Foster

Clare Wilson

Julia S Gauer

Rui-Gang Xu

Mark J Howard

Iain W Manfield

Robert Ariens

Khalid Naseem

Lewis R Vidler

Helen Philippou

Richard Foster

Affiliations

Soon will be listed here.

Abstract

The GPVI platelet receptor was recently validated as a safe antiplatelet target for the treatment of thrombosis using several peptidic modulators. In contrast, few weakly potent small-molecule GPVI antagonists have been reported. Those that have been published often lack evidence for target engagement, and their biological efficacy cannot be compared because of the natural donor variability associated with the assays implemented. Herein, we present the first side-by-side assessment of the reported GPVI small-molecule modulators. We have characterized their functional activities on platelet activation and aggregation using flow cytometry as well as light transmission and electrical impedance aggregometry. We also utilized microscale thermophoresis (MST) and saturation transfer difference (STD) NMR to validate GPVI binding and have used this along with molecular modeling to suggest potential binding interactions. We conclude that of the compounds examined, losartan and compound are currently the most viable GPVI modulators.

Citing Articles

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