GPVI inhibition: Advancing antithrombotic therapy in cardiovascular disease

Figures

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  Figure 1. GPVI inhibition by glenzocimab and revacept. (A) Clustering of GPVI monomers and dimers by multivalent ligands, such as collagen, results in sustained signalling and platelet activation. The FcR-γ chain associates with GPVI and contains the ITAM sequences that are critical for phosphorylation-induced signalling. Figure adapted from Slater and Jandrot-Perrus.74 (B) Glenzocimab binds to the D2 domain of GPVI and blocks dimerization and ligand binding. This results in potent inhibition of receptor clustering. (C) Revacept mimics extracellular GPVI and competes with the membrane-bound GPVI for ligand binding. GPVI, glycoprotein VI; ITAM, immunoreceptor tyrosine-based activation motif.

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  Figure 2. Alternative approaches to inhibiting GPVI signalling. (A) GPVI signalling requires the interaction of both SFKs and the FcR-γ chain to the intracellular tails of GPVI. SFKs phosphorylate the ITAM tyrosine residues of the FcR-γ chain upon GPVI activation, which leads to further downstream signalling. Blocking the interaction of GPVI with SFKs or the FcR-γ chain would lead to signal inhibition. (B) GPVI is cleaved by ADAM10 just before the transmembrane region in a process known as shedding. Extracellular GPVI is released from the platelet surface, leaving behind truncated GPVI consisting of transmembrane and intracellular region. This cleaved construct is no longer signal active due to it not being able to be clustered by ligands. ADAM10-induced shedding is mediated by Tspan5 and 33. (C) SFKs phosphorylate the ITAM sequences of the FcR-γ chain upon GPVI activation. This induces downstream signalling events. G6b-B associates with both GPVI and the intracellular phosphatase SHP2. Bringing SHP2 into proximity with the FcR-γ chain promotes dephosphorylation of the ITAM sequences and inhibits further downstream signalling. ADAM10, a disintegrin and metalloproteinase 10; GPVI,…