Structural principles of insulin formulation and analog design: A century of innovation

dc.contributor.authorJarosinski, Mark A.
dc.contributor.authorDhayalan, Balamurugan
dc.contributor.authorChen, Yen-Shan
dc.contributor.authorChatterjee, Deepak
dc.contributor.authorVaras, Nicolás
dc.contributor.authorWeiss, Michael A.
dc.contributor.departmentBiochemistry and Molecular Biology, School of Medicineen_US
dc.date.accessioned2023-03-21T15:04:41Z
dc.date.available2023-03-21T15:04:41Z
dc.date.issued2021-10
dc.description.abstractBackground: The discovery of insulin in 1921 and its near-immediate clinical use initiated a century of innovation. Advances extended across a broad front, from the stabilization of animal insulin formulations to the frontiers of synthetic peptide chemistry, and in turn, from the advent of recombinant DNA manufacturing to structure-based protein analog design. In each case, a creative interplay was observed between pharmaceutical applications and then-emerging principles of protein science; indeed, translational objectives contributed to a growing molecular understanding of protein structure, aggregation and misfolding. Scope of review: Pioneering crystallographic analyses-beginning with Hodgkin's solving of the 2-Zn insulin hexamer-elucidated general features of protein self-assembly, including zinc coordination and the allosteric transmission of conformational change. Crystallization of insulin was exploited both as a step in manufacturing and as a means of obtaining protracted action. Forty years ago, the confluence of recombinant human insulin with techniques for site-directed mutagenesis initiated the present era of insulin analogs. Variant or modified insulins were developed that exhibit improved prandial or basal pharmacokinetic (PK) properties. Encouraged by clinical trials demonstrating the long-term importance of glycemic control, regimens based on such analogs sought to resemble daily patterns of endogenous β-cell secretion more closely, ideally with reduced risk of hypoglycemia. Major conclusions: Next-generation insulin analog design seeks to explore new frontiers, including glucose-responsive insulins, organ-selective analogs and biased agonists tailored to address yet-unmet clinical needs. In the coming decade, we envision ever more powerful scientific synergies at the interface of structural biology, molecular physiology and therapeutics.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationJarosinski MA, Dhayalan B, Chen YS, Chatterjee D, Varas N, Weiss MA. Structural principles of insulin formulation and analog design: A century of innovation. Mol Metab. 2021;52:101325. doi:10.1016/j.molmet.2021.101325en_US
dc.identifier.urihttps://hdl.handle.net/1805/31994
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.molmet.2021.101325en_US
dc.relation.journalMolecular Metabolismen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0*
dc.sourcePMCen_US
dc.subjectProtein engineeringen_US
dc.subjectPharmacodynamicsen_US
dc.subjectInsulin actionen_US
dc.subjectInsulin signalingen_US
dc.subjectMolecular pharmacologyen_US
dc.titleStructural principles of insulin formulation and analog design: A century of innovationen_US
dc.typeArticleen_US
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