Discovery and design of novel insulin evologs from venomous marine cone snails

SUMMARY Insulin is a pancreatic peptide hormone that is of critical importance for glucose homeostasis. Disruption of insulin production or function can result in diabetes mellitus. Insulin therapy is the only effective treatment for type 1 diabetes (T1D) and is used by many people with type 2 diabetes (T2D) and some individuals with gestational diabetes (GDM). Despite major advances in insulin therapy, achieving efficient glycemic control to prevent short- and long-term complications remains a major challenge in diabetes management. This is in part due to the fact that insulin and its current therapeutic analogs self-associate into dimers and hexamers that form subcutaneous depots, which delays their onset of action and leads to prolonged duration of action. Our recent discovery of specialized monomeric insulins from the venom of fish-hunting cone snails that rapidly lower blood glucose in animal models of diabetes provides the unique opportunity to address these persistent limitations of current diabetes therapeutics. Furthermore, shaped by millions of years of predator-prey evolution, venom insulins have evolved unique ways of engaging with the vertebrate insulin receptor (hIR), thus providing a unique toolset to study diverse molecular modes of hIR activation. Proof of concept for the high translational impact of this proposal is provided by Con-Insulin G1, our first discovered venom insulins that revealed the existence of a minimized insulin binding motif at the hIR and has already led to the design of a new therapeutic prandial insulin candidate. Our recent preliminary data demonstrates that Con-Ins G1 is only one of > 20 diverse insulins evolved by fish-hunting cone snails. We hypothesize that each one of these insulins represents a novel scaffold for the rational design of improved insulin therapeutics. The aim of this proposal is to survey the entire chemical diversity of naturally evolved insulin analogs (so-called evologs) for the discovery and development of new insulin drug candidates with advantageous properties over existing analogs (i.e., improved stability profiles, faster onset of action, reduced rates of post-injection hypoglycemia, and potentially improved metabolic signaling). We anticipate that these candidates have the potential to significantly improve diabetes therapy and enhance the performance of closed-loop systems in the future.