Snake- and spider-venom-derived toxins as lead compounds for drug development

Abstract

Snake and spider venoms have been developed by nature as a defense mechanism against predators or to immobilize their prey by blocking the cardiovascular, respiratory, and/or nervous systems. Consequently, predators are deterred from approaching their prey by painful sensations. At a molecular level, the targeted physiological systems are blocked or stimulated by peptide toxins which, once injected into the body, modulate, though not exclusively, important cell membrane ion channels and receptors. Millions of years of constant evolution have led to the evolvement of complex venom libraries of optimized protein toxins, making them more potent, more selective, resistant to proteases, less immunogenic, and improved in terms of pharmacokinetic (PK) properties. The resulting advantage is that they induce long-term and potent pharmacodynamic (PD) effects toward unique molecular targets of therapeutic importance such as coagulation cascade proteins, receptors, and ionic channels. This optimization process has been enabled by the diversification of peptide sequences (mainly by gene duplication) and an upscaling of the complexity of toxin peptide scaffold structures, through implementation of multiple disulfide bridges and sequence-active motif diversification, leading to a wide diversity of chemical structures. This combination of pharmaceutical properties has made venom toxins valuable both as pharmacological tools and as leads for drug development. These highly tunable molecules can be tailored to achieve desirable biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. This brief overview provides basic definitions, rules, and methodologies and describes successful examples of a few drugs developed from snake toxins that are currently used in the clinic for therapy of several diseases as well as new molecular entities in clinical development based on spider-venom-derived peptide toxins.