Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2

Foteini-Nafsika Damaskinaki, Luis Moran Lara, Angel García, Barrie Kellam, Steve Watson

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
118 Downloads (Pure)

Abstract

GPVI and CLEC-2 have emerged as promising targets for long-term prevention of both arterial thrombosis and thrombo-inflammation with a decreased bleeding risk relative to current drugs. However, while there are potent blocking antibodies of both receptors, their protein nature comes with decreased bioavailability, making formulation for oral medication challenging. Small molecules are able to overcome these limitations, but there are many challenges in developing antagonists of nanomolar potency, which is necessary when considering the structural features that underlie the interaction of CLEC-2 and GPVI with their protein ligands. In this review, we describe current small-molecule inhibitors for both receptors and strategies to overcome such limitations, including considerations when it comes to in silico drug design and the importance of complex compound library selection.
Original languageEnglish
Pages (from-to)744-752
JournalPlatelets
Volume32
Issue number6
Early online date7 Jan 2021
DOIs
Publication statusE-pub ahead of print - 7 Jan 2021

Bibliographical note

Funding: This work was supported by the British Heart Foundation [CH03/003]; European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant [766118].

Keywords

  • CLEC-2
  • GPVI
  • antagonists
  • platelets
  • small molecule inhibitors

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