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

Area of Science:

• Biochemistry
• Endocrinology
• Structural Biology

Background:

• Human insulin and its analogs self-associate into dimers and hexamers, delaying action and complicating diabetes management.
• A previously identified monomeric, insulin-like peptide from cone-snail venom showed moderate bioactivity.

Purpose of the Study:

• To develop a structurally minimal, full-potency human insulin analog.
• To investigate the role of the B-chain C-terminal octapeptide in insulin function.

Main Methods:

• Utilized structural biology insights to design a novel insulin analog (mini-Ins).
• Introduced four specific mutations to compensate for the absence of the octapeptide.
• Assessed receptor binding affinity, in vitro insulin signaling, and in vivo bioactivity.

Main Results:

• Mini-Ins demonstrated monomeric properties and maintained similar receptor binding affinity to human insulin.
• Despite lacking the octapeptide, mini-Ins exhibited comparable in vitro and in vivo bioactivities to human insulin.
• The PheB24-PheB25-TyrB26 aromatic triplet was found to be dispensable for full bioactivity.

Conclusions:

• Mini-Ins represents a structurally minimal, full-potency insulin analog.
• The development of mini-Ins opens new avenues for therapeutic insulin design.
• This work highlights the dispensability of the B-chain C-terminal octapeptide for insulin's biological activity.