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

Nat Struct Mol Biol. 2020 Jul;27(7):615-624. doi: 10.1038/s41594-020-0430-8. Epub 2020 Jun 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antigens, CD / chemistry*
  • Antigens, CD / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Insulin / analogs & derivatives
  • Insulin / chemistry*
  • Insulin / metabolism
  • Insulin / pharmacology
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Mollusk Venoms / chemistry*
  • Mollusk Venoms / genetics
  • Mollusk Venoms / metabolism*
  • Mollusk Venoms / pharmacology
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Conformation
  • Rats, Sprague-Dawley
  • Receptor, Insulin / chemistry*
  • Receptor, Insulin / metabolism
  • Structure-Activity Relationship
  • Tyrosine


  • Antigens, CD
  • Insulin
  • Mollusk Venoms
  • Peptides
  • Tyrosine
  • INSR protein, human
  • Receptor, Insulin