Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity

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HighlightsAn insulin receptor antagonist conjugated to insulin results in an insulin agonist with reduced maximal activity.Mutation of a single amino acid within the antagonist leads to a laddered set of insulin partial agonists.These peptides constitute a novel approach to study the relationship of maximal in vitro activity with in vivo pharmacology.In the treatment of insulin-dependent diabetes the risk of a fatal insulin overdose is a persistent fear to most patients. In order to potentially reduce the risk of overdose, we report the design, synthesis, and biochemical characterization of a set of insulin analogs designed to be fractionally reduced in maximal agonism at the insulin receptor isoforms. These analogs consist of native insulin that is site-specifically conjugated to a peptide-based insulin receptor antagonist. The structural refinement of the antagonist once conjugated to insulin provided a set of partial agonists exhibiting between 25 and 70% of the maximal agonism of native insulin at the two insulin receptor isoforms, with only slight differences in inherent potency. These rationally-designed partial agonists provide an approach to interrogate whether control of maximal activity can provide glycemic control with reduced hypoglycemic risk.

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