A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
journal contribution
posted on 2025-11-21, 04:40 authored by X Xiong, JG Menting, MM Disotuar, Nicholas SmithNicholas Smith, CA Delaine, G Ghabash, R Agrawal, X Wang, X He, SJ Fisher, CA MacRaild, Raymond Norton, J Gajewiak, BE Forbes, Brian SmithBrian Smith, H Safavi-Hemami, B Olivera, MC Lawrence, DHC ChouHuman 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.<p></p>
Funding
X.X. is a Juvenile Diabetes Research Foundation Postdoctoral Fellow. N.A.S. acknowledges receipt of an Australian Research Training Scholarship. R.S.N acknowledges fellowship support from the Australian National Health and Medical Research Council. Part of this work was undertaken using resources from the National Computational Infrastructure, which is supported by the Australian Government and provided through Intersect Australia Ltd, and through the HPC-GPGPU Facility, which was established with the assistance of a Linkage Infrastructure, Equipment and Facilities grant (LE170100200). This work is supported by NIDDK (DK120430, GM125001 to D.H.C.), the Juvenile Diabetes Research Foundation (5-CDA-2018-572-A-N to D.H.C. and 1-INO-2017-441-A-N to H.S.H.), the Australian National Health and Medical Research Council (NHMRC) Project grant nos. APP1143546 (to M.C.L., R.S.N., B.J.S., B.E.F. and D.H.C.) and APP1099595 (to M.C.L.). M.C.L.'s research is also made possible at The Walter and Eliza Hall Institute of Medical Research through Victorian State Government Operational Infrastructure Support and the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme.
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