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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Venomics: Targeted Drug Discovery and Lead OptimisationUsing Animal VenomsReto Stöcklin*, Estelle Bianchi, Daniel Biass, Cécile Cros,Dominique Koua, Frederic Perret, Aude Violette, andPhilippe FavreauAtheris Laboratories, case postale 314, CH-1233, Bernex-Geneva, SwitzerlandIntroductionVenoms are rich mixtures of peptides and proteins evolved by Nature to catch and digestpreys or for protection against predators. They represent extensive sources of potent andselective bioactive compounds to discover and develop new drugs. Conventionalbioactivity-guided strategies are time consuming and require large amounts of material. Incontrast, state-of-the-art proteomic, transcriptomic and post-genomic technologies coupledto bioinformatics can swiftly generate abundant and valuable data using minimal sampleamounts.Strategy and Case StudiesIn a typical drug discovery project, we use our databases to select venoms offering higherchances to generate hits for a given target. The venoms are pre-fractionated using specificmethods and natural libraries are made ready for bioassays. The fraction composition isoften investigated in parallel on our mass spectrometry and bioinformatics platform withdatabase matching. Stringent criteria are used to pick out fractions for deconvolution, andhits are synthesised at an early stage to generate synthetic libraries of bioactive candidates.After deeper evaluations, selected leads undergo optimisation through drug design andstructure-function studies. Here again, we developed an original approach: our platform isdesigned to screen related venoms and other organisms to identify natural analogues of thelead compound in order to exploit what nature has optimised through million years ofnatural selection.Our bioactivity-guided, structure-driven and biocomputing-assisted Venomicsstrategies are illustrated through the discovery of novel sarafotoxins (endothelin-typepeptides), bradykinin-potentiating peptides (BPP’s) and novel antimicrobial peptides. Thepresentation will also focus on “CONCO – the cone snail genome project for health”, thefirst fully integrated Venomics project, which is devoted to venomous marine snails.Endothelins are mini-proteins of 21 amino acids with two disulfide bonds that play akey role in vascular homeostasis and are strong vasoconstrictors. Their over-expressionleads to hypertension and vascular diseases. Sarafotoxins from burrowing asp snake toxinsare homologous to endothelin peptides but lethal. By screening the proprietary databaseToxEnter, a closely related species (Atractaspis microlepidota) was identified [1].LC-ESI-MS and de novoMS/MS analysis of thevenom revealed typicalC-terminal sequences ofsarafotoxins and endothelinsprolonged byadditional tripeptide(Figure 1). The structurerevealed an additionalC-terminal alpha-helixregion crucial for interactionwith endothelinreceptors. The preliminarystudies suggestedbinding to endothelinreceptors with no inductionof activity (inhibitoryeffect).Fig. 1. MS/MS spectrum of sarafotoxin C-terminal sequence.Endothelin560