The conformational “life cycle” of the insulin molecule exhibits distinct determinants of foldability (nascent biosynthesis in the pancreatic beta-cell), trafficking (between compartments in the beta-cell secretory pathway), self-assembly and storage (in glucose-regulated secretory granules), receptor binding (at target cells) and degradation (on internalization of the hormone-receptor complex). These multiple biological processes impose independent evolutionary constraints, which may be at odds or interlocking—in either case limiting divergence of vertebrate insulin sequences. Because native sequences are not optimized for chemical or physical stability, the susceptibility of the hormone to degradation in pharmaceutical formulations has limited their compatibility with next-generation delivery devices and imposed a costly cold chain of global transport. Here, we present biophysical studies of insulin analogs as a foundation for non-standard design of ultra-stable insulin analogs. Emphasis will be placed on foundational principles of biophysical chemistry with validation by structural methods (multidimensional solid-state and solution-state NMR spectroscopy, X-ray crystallography and single-particle cryoEM-based image reconstruction) and their extension by molecular-dynamics (MD) simulations. Attention will be paid to mechanism-based “counter-design” with respect to protein fibrillation and undesirable signaling properties. Prospects for clinical translation will be discussed based on the expanded sequence space of unnatural amino acids.

Physico-chemical design principles of ultra-stable insulin analogs

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