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

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.

Keywords:

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

Acknowledgements

F.N. D. is supported by a COMPARE PhD studentship, L.A.M receives funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 766118. SPW holds a BHF Chair (CH03/003). We thank Eleyna Martin and Alex Slater for their critical evaluation of the manuscript and useful discussions during the writing of the manuscript, and Jon Gibbins for critical comments on the manuscript.

Additional information

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].