Novo Nordisk Research Center, Indianapolis, Indiana 46241, United States.
Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.
J Med Chem. 2020 Apr 9;63(7):3447-3460. doi: 10.1021/acs.jmedchem.9b01493. Epub 2019 Dec 18.
Glucagon counters insulin's effects on glucose metabolism and serves as a rescue medicine in the treatment of hypoglycemia. Acute hypoglycemia, a common occurrence in insulin-dependent diabetes, is the central obstacle to correcting high blood glucose, a primary cause of long-term microvascular complications. As a result, there has been a resurgence of interest in improved glucagon therapy, including nonconventional liquid formulations, alternative routes of administration, and novel analogs with optimized biophysical properties. These options collectively minimize the complexity of glucagon delivery and enable its application in ways not feasible with conventional emergency rescue kits. These advances have indirectly promoted the integrated use of glucagon agonism with other hormones in a manner that runs counter to the long-standing pursuit of glucagon antagonism. This review summarizes novel approaches to glucagon optimization, methods with potential application to the broader family of therapeutic peptides, where biophysical challenges may be encountered.
胰高血糖素拮抗胰岛素对葡萄糖代谢的作用，是治疗低血糖的急救药物。胰岛素依赖型糖尿病常发生急性低血糖，这是纠正高血糖的主要障碍，而高血糖是长期微血管并发症的主要原因。因此，人们对改善胰高血糖素治疗重新产生了兴趣，包括非传统的液体制剂、替代给药途径以及优化了生物物理特性的新型类似物。这些选择共同降低了胰高血糖素给药的复杂性，并使其能够以常规急救包不可行的方式应用。这些进展间接促进了以与长期追求的胰高血糖素拮抗相反的方式将胰高血糖素激动作用与其他激素综合使用。这篇综述总结了优化胰高血糖素的新方法，这些方法可能适用于更广泛的治疗性肽家族，在这些家族中可能会遇到生物物理方面的挑战。
