A structurally minimized yet fully active insulin based on cone-snail venom insulin principles Academic Article uri icon

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.

authors

  • Xiong, X
  • Menting, JG
  • Disotuar, MM
  • Smith, Nicholas
  • Delaine, CA
  • Ghabash, G
  • Agrawal, R
  • Wang, X
  • He, X
  • Fisher, SJ
  • MacRaild, CA
  • Norton, Raymond
  • Gajewiak, J
  • Forbes, BE
  • Smith, Brian
  • Safavi-Hemami, H
  • Olivera, B
  • Lawrence, MC
  • Chou, DHC

publication date

  • 2020