Abstract by Sophie Heiden Laugesen

Cone snail venom contains unique insulin peptides that can induce hypoglycemia in prey, a feature that can be exploited for therapeutic insulin design. Unlike human insulin, some cone snail insulins lack the C-terminus of the B chain, which is essential for the activity of human insulin but can still potently activate the human insulin receptor (IR), suggesting novel avenues for insulin analog development.

To overcome the challenges of chemically synthesizing cone snail insulins, I aimed to establish a recombinant expression system for producing correctly folded cone snail venom insulins and their hybrid analogs.

Utilizing a library of over 100 diverse cone snail insulin sequences, I employed the csCyDisCo expression system, which has been optimized for the expression of cone snail venom peptides for the recombinant production of selected insulins.

My efforts have led to the successful expression and purification of select cone snail venom insulins, including the structurally complex Con-Ins Ro3. However, issues related to the oxidative state of the proteins were encountered, which hindered the yield of properly folded insulins.

I also designed and tested a cone snail human insulin hybrid analog. This included Con-Ins G1 [A2I], which demonstrated a tendency for increased potency at the IR in preliminary assays. Furthermore, initial experiments suggested a synergistic effect between Con-Ins G1 and human insulin in activating the IR, suggesting a potential avenue for enhanced therapeutic strategies.