Abstract
Snake venoms are attractive natural sources for drug discovery and development, with a number of substances either in clinical use or in research and development. These drugs were developed based on RGD-containing snake venom disintegrins, which efficiently antagonize fibrinogen activation of αIIbβ3 integrin (glycoprotein GP IIb/IIIa). Typical examples of anti-platelet drugs found in clinics are Integrilin (Eptifibatide), a heptapeptide derived from Barbourin, a protein found in the venom of the American Southeastern pygmy rattlesnake and Aggrastat (Tirofiban), a small molecule based on the structure of Echistatin, and a protein found in the venom of the saw-scaled viper. Using a similar drug discovery approach, linear and cyclic peptides containing the sequence K(R)TS derived from VP12, a C-type lectin protein found in the venom of Israeli viper venom, were used as a template to synthesize Vipegitide, a novel peptidomimetic antagonist of α2β1 integrin, with anti-platelet activity. This review focus on drug discovery of these anti-platelet agents, their indications for clinical use in acute coronary syndromes and percutaneous coronary intervention based on several clinical trials, as well as their adverse effects.
Highlights
Integrins are a large group of receptors composed of different combinations of the α and β chains.These receptors mediate cell adhesion to extracellular matrix (ECM) proteins and are involved in cell-cell interactions
Disintegrins are a group of low molecular weight, polypeptides folded by cysteine bridges that modulate cell adhesion, migration, apoptosis, platelet aggregation, and angiogenesis
Disintegrins with integrin αIIbβ3 andα2β1, leading to drug development of small-molecule that were successful in clinical trials
Summary
Integrins are a large group of receptors composed of different combinations of the α and β chains These receptors mediate cell adhesion to extracellular matrix (ECM) proteins and are involved in cell-cell interactions. ECM protein ligands bind integrins through the Arg-Gly-Asp (RGD) sequence motif, surrounded by disulphide bonds and neighbored by charged amino acids. Binding of ECM ligands to the integrin receptor propagates signaling across the membrane (‘outside-in’) to activate cytoplasmic protein kinases and cytoskeletal-signaling cascades. These biochemical activities control fundamental cell physiology processes such as survival adherence, movement, growth, and differentiation [1,2,3]. The understanding of the mechanism of action of integrins paralleled the discovery of proteins from snake venoms, known as the disintegrins, which function as potent inhibitors of platelet aggregation and integrin receptor-dependent cell adhesion [4,5]
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