A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Nature Structural and Molecular Biology |
Volume | 27 |
Pages (from-to) | 615-624 |
ISSN | 1545-9993 |
DOIs | |
Publication status | Published - 2020 |
Bibliographical note
Author Correction: https://www.nature.com/articles/s41594-020-0460-2
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374640/pdf/nihms-1582978.pdf
Accepted author manuscript
ID: 244531737