Two 57-residue peptides containing four disulfide bonds were recently isolated from black mamba venom (Dendroaspis polylepis polylepis) using a screen to discover novel acid-sensing ion channel (ASIC) inhibitors (1). Mambalgins are potent, rapid and reversible inhibitors of ASIC channels and produce effective analgesia by targeting both central neurons and primary nociceptors through different ASIC channel subtypes (1). Although they have only limited sequence similarity with previously identified snake toxins and no homology with other toxins targeting ASICs (e.g. PcTx1 or APETx2) they have been proposed to adopt a three-finger toxin fold. Here we describe the chemical synthesis and progress towards the first NMR solution structure of Mambalgin-2, which will form the basis for detailed structure-activity studies of this class of molecules in the future.
1. Diochot, S., Baron, A., Salinas, M., Douguet, D., Scarzello, S., Dabert-Gay, A-S., Debayle, D., Friend, V., Alloui, A., Lazdunski, M. and Lingueglia, E. (2012) Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature, 490: 552-555.
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