Thesis (Ph.D.) - Indiana University, Biochemistry, 2015Insulin-dependent diabetes requires the daily administration of insulin to regulate blood glucose. Unfortunately, insulin possesses a narrow therapeutic index which represents a risk for overdose and life-threatening hypoglycemia. This research investigates the synthesis and biological characterization of insulin-based analogs that activate the insulin receptor with high potency, but varying degrees of maximal activity. These analogs are dimeric peptides that consist of native insulin and a covalently bound insulin receptor antagonist. Structure-activity analysis revealed a key amino acid within the antagonist, and mutations at this single position control the maximal activity of the heterodimer. These analogs may represent a route to a safer insulin therapy, through selection of an optimized analog that has diminished activity relative to the native hormone
