A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
Journal Title
Nature Structural & Molecular Biology
Publication Type
Journal epub ahead of print
Abstract
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.
Publisher
NPG
WEHI Research Division(s)
Structural Biology
PubMed ID
32483339
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-07-02 01:44:21
Last Modified: 2020-07-02 02:39:11
An error has occurred. This application may no longer respond until reloaded. Reload 🗙