TY  - JOUR
AU  - Xiong, X
AU  - Menting, JG
AU  - Disotuar, MM
AU  - Smith, NA
AU  - Delaine, CA
AU  - Ghabash, G
AU  - Agrawal, R
AU  - Wang, X
AU  - He, X
AU  - Fisher, SJ
AU  - MacRaild, CA
AU  - Norton, RS
AU  - Gajewiak, J
AU  - Forbes, BE
AU  - Smith, BJ
AU  - Safavi-Hemami, H
AU  - Olivera, B
AU  - Lawrence, MC
AU  - Chou, DH-C
Y2  - 2020/12/16
Y1  - 2020/06/01
SN  - 1545-9993
UR  - http://hdl.handle.net/11343/254484
AB  - 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.
LA  - English
PB  - NATURE PUBLISHING GROUP
T1  - A structurally minimized yet fully active insulin based on cone-snail venom insulin principles
DO  - 10.1038/s41594-020-0430-8
IS  - Nature Structural and Molecular Biology
VL  - 27
IS  - 7
SP  - 615-+
OP  - LE170100200
ER  -