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

Publikation: Bidrag til tidsskriftTidsskriftartikelfagfællebedømt

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

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.

TidsskriftNature Structural and Molecular Biology
Sider (fra-til)615-624
StatusUdgivet - 2020

ID: 244531737