Journal Article

A structurally minimized yet fully active insulin based on cone-snail venom insulin principles

Lawrence, Michael C, Xiong Xiaochun, Chou, Danny Hung-Chieh, Disotuar, Maria M, Delaine, Carlie A, Agrawal Rahul, Norton, Raymond S, Olivera Baldomero, Safavi-Hemami Helena, Wang, Xiaomin, Ghabash Gabrielle, bes, Briony E, Menting John G, Gajewiak Joanna, Smith, Nicholas A, MacRaild, Christopher A, He, Xiao, Fisher, Simon J, Smith, Brian J

2020

Overview

Human insulin and its current therapeutic analogs all show propensity, albeit varyingly, to self-associate into dimers and hexamers, which delays their onset of action and makes blood glucose management difficult for people with diabetes. Recently, we described a monomeric, insulin-like peptide in cone-snail venom with moderate human insulin-like bioactivity. Here, with insights from structural biology studies, we report the development of mini-Ins—a human des-octapeptide insulin analog—as a structurally minimal, full-potency insulin. Mini-Ins is monomeric and, despite the lack of the canonical B-chain C-terminal octapeptide, has similar receptor binding affinity to human insulin. Four mutations compensate for the lack of contacts normally made by the octapeptide. Mini-Ins also has similar in vitro insulin signaling and in vivo bioactivities to human insulin. The full bioactivity of mini-Ins demonstrates the dispensability of the PheB24–PheB25–TyrB26 aromatic triplet and opens a new direction for therapeutic insulin development.Insights from structural biology lead to the development of mini-Ins—a human des-octapeptide insulin analog that is monomeric and has receptor binding affinity and in vitro and in vivo activities comparable to those of human insulin.

• Publisher: Nature Publishing Group
• Subject: Affinity / Binding / Biological activity / Biology / Blood glucose / Diabetes mellitus / Dimers / Hexamers / Insulin / Mutation / Receptors / Venom