Full list of publication: https://www.ncbi.nlm.nih.gov/pubmed/?term=safavi-hemami
Venom Peptide Discovery
Over the past five years we have conducted a world-wide field collection effort to sequence more than 100 different species of venomous marine gastropods by transcriptomics and proteomics (right image: shells of sequenced marine gastropods). By applying several different computational pipelines we have identified more than 40,000 toxin sequences including many entirely new gene families of yet unknown function. This represents one of the largest collection and sequencing effort of a venomous genus to date. We have characterized several of these new toxins and are currently developing bioinformatic tools to identify the most promising future drug leads from these large datasets.
Venom Insulins – Discovery, Evolution and Biomedical Applications
We discovered that Conus geographus, a cone snail species that releases venom into the water to sedate its prey, uses an unusually small and heavily post-translationally modified insulin, Con-Ins G1, for prey capture. When released into the water, this insulin rapidly induces hypoglycemic shock in fish, the prey of C. geographus. Structure-function analysis of this unique insulin has already provided novel insights into insulin receptor activation and uniquely informed on the design of a fast-acting drug lead for type 1 and late-stage type 2 diabetes. Using our large venom datasets we have since been able to show that venom insulins are widely distributed in cone snail venoms and have identified a panel of additional fast-acting venom insulins that bind to and activate the human insulin receptor. We anticipate that these diverse insulins will serve as unique pharmacological tools for studying insulin receptor activation and isoform distribution and hold tremendous opportunity for current efforts into the design of novel fast-acting therapeutics for diabetes.
At any given time, hundreds of highly modified, structurally complex peptides are biosynthesized in the venom gland of cone snails. We have had a long-standing interest in identifying these enzymes and utilizing evolutionary and functional information of these enzymes to generate optimized venom expression systems. Together with Prof. Ellgaard at the University of Copenhagen we have commenced to successfully express many of the new toxins we have recently discovered, including venom insulins and other complex peptides with multiple disulfide bonds.