Structure-activity Relationships of Snake Toxins Targeting Platelet Receptors, Glycoprotein Ib-IX-V and Glycoprotein VI

Initiation of thrombus formation involves the platelet adhesion receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor (vWF) and collagen, respectively. These interactions trigger intracellular signals leading to degranulation, elevation of cytosolic Ca2+, cytoskeletal rearrangements, and “inside-out” activation of the integrin, GPIIb-IIIa (αIIbβ3) that binds von Willebrand Factor (vWF) or fibrinogen and mediates platelet aggregation. GPIba (the vWF-binding subunit of GPIb-IX-V) of the leucine-rich repeat protein family and GPVI of the immunoglobulin superfamily not only have a parallel physiological function, but recent studies of these receptors have revealed structureactivity relationships amongst snake venom toxins which target them. Two families of venom proteins, the C-type lectinlike proteins and metalloproteinase-disintegrins, target GPIbα, GPVI and / or the collagen-binding integrin, GPIa-IIa (α2β1). Members of the C-type lectin family interact specifically with GPIba (echicetin, alboaggregin-B, agglucetin), GPVI (convulxin, ophioluxin) or GPIa-IIa (rhodocetin), whereas related proteins accomplish dual receptor occupancy and bind GPVI and GPIba (alboaggregin-A, alboluxin), or GPIbα and GPIa-IIa (aggretin). These latter venom proteins mimic physiological ligands, vWF or collagen, which also recognize more than one receptor. Similarly, metalloproteinasedisintegrin family proteins target GPIbα (mocarhagin, crotalin), GPVI (alborhagin) or GPIa-IIa (jararhagin), resulting in inhibition or induction of platelet aggregation by proteolytically dependent or independent mechanisms. Anti-thrombotics based on snake venom GPIIb-IIIa inhibitors have been investigated clinically, however analogous proteins recognizing GPIb-IX-V or GPVI are yet to be therapeutically exploited.