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

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 novel direction for therapeutic insulin development.

Therapeutic Potential of Peptides Derived from Animal Venoms: Current Views and Emerging Drugs for Diabetes

“… 139 , 140 Additionally, unlike human insulin, Cons-Ins G1 has a lower affinity for the primary binding site on the human insulin receptor (hIR), with a preferential affinity for the secondary binding site, suggesting an alternative mechanistic approach to hIR activation. 141 Furthermore, this insulin peptide contains post-translational modifications in the A and B chain, namely a γ-carboxylated glutamate residue and a hydroxylated proline residue, respectively, which have been hypothesised to increase biological activity. 141 In this regard, the crystal structure of Con-Ins G1 in comparison to human insulin has been described.…”

“… 141 Furthermore, this insulin peptide contains post-translational modifications in the A and B chain, namely a γ-carboxylated glutamate residue and a hydroxylated proline residue, respectively, which have been hypothesised to increase biological activity. 141 In this regard, the crystal structure of Con-Ins G1 in comparison to human insulin has been described. 141 The discovery of Cons-Ins G1 has led to the synthesis of a new recombinant insulin analogue, with an extremely fast onset of action due to its smaller size.…”

Curses or Cures: A Review of the Numerous Benefits Versus the Biosecurity Concerns of Conotoxin Research

“…Insulin receptor Minimized binding motif at the insulin receptor [65] Receptor binding and drug design [92] κ-PVIIA Voltage-gated K + channels…”

A Combined Transcriptomics and Proteomics Approach Reveals the Differences in the Predatory and Defensive Venoms of the Molluscivorous Cone Snail Cylinder ammiralis (Caenogastropoda: Conidae)

“…In addition to conotoxins, species of the genus Gastridium , which engulf schools of small fishes with the rostrum before injecting venom through the proboscis [ 18 ], have evolved a specialized strategy to sedate fish prey that includes an insulin mimic to cause hypoglycemic shocks [ 22 ]. Interestingly, the monomeric structure of this insulin has been used to design a small and fully active insulin analog to treat human diabetes [ 23 ]. Apart from peptides, the venom of the West African species Genuanoconus genuanus produces a guanine derivative, genuanine, with toxic properties, indicating that the overall complexity of cone snail venom cocktails is far from being fully described [ 24 ].…”