Synthesis and Biological Assessment of Insulin-Like Analogs with Differential Activity at the Insulin and IGF-1 Receptors

摘要

Insulin is a physiological hormone of seminal importance to the utilization, storage and mobilization of glucose. Over the course of nearly a century millions of patients with diabetes have depended upon this medicine as a life-saving therapy. The advent of rDNA biosynthesis provided human insulin in virtually unlimited quantity and modest expense relative to most rDNA-derived medicines. More importantly, it provided a mechanism by which improved insulin analogs could be synthesized, evaluated and registered as new medicines. The development of biosynthetic insulin analogs has provided improved efficacy, safety and convenience to insulin-requiring diabetics. In a broader manner these protein analogs represent the first step in elevating protein medicinal chemistry from an academic endeavor to a clinical reality. Chemical biotechnology (biosynthesis with unnatural amino acids) provides new opportunity for expanding the insulin structure-activity relationship and through it the development of protein analogs possessing superior pharmaceutical properties, at a scale and cost competitive with conventional biotechnology.