Journal article
An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein
MD Glidden, K Aldabbagh, NB Phillips, K Carr, YS Chen, J Whittaker, M Phillips, NP Wickramasinghe, N Rege, M Swain, Y Peng, Y Yang, MC Lawrence, VC Yee, F Ismail-Beigi, MA Weiss
Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2018
Abstract
Thermal degradation of insulin complicates its delivery and use. Previous efforts to engineer ultra-stable analogs were confounded by prolonged cellular signaling in vivo, of unclear safety and complicating mealtime therapy. We therefore sought an ultra-stable analog whose potency and duration of action on intravenous bolus injection in diabetic rats are indistinguishable from wild-type (WT) insulin. Here, we describe the structure, function, and stability of such an analog, a 57-residue single-chain insulin (SCI) with multiple acidic substitutions. Cell-based studies revealed native-like signaling properties with negligible mitogenic activity. Its crystal structure, determined as a novel zi..
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Funding Acknowledgements
This work, a contribution of the Cleveland Center for Membrane and Structural Biology and CWRU Institute for the Science of Origins, was supported in part by National Institutes of Health Grants R01 DK040949 and R01 DK069764 (to M.A.W.), Australian National Health and Medical Research Council Project Grant APP1058233 (to M.C.L.), Victorian State Government Operational Infrastructure Support, and funding from the Australian NHMRC Independent Research Institutes Infrastructure Support Scheme, both to his institution. M.A.W. has equity in Thermalin Diabetes, LLC (Cleveland, OH), where he serves as Chief Innovation Officer; he has also been a consultant to Merck Research Laboratories and DEKA Research & Development Corp. N.B.P. and F.I.-B. are consultants to Thermalin Diabetes, LLC. Part of M.C.L.'s research is funded by Sanofi (Germany). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.