An Evolutionary Approach to Therapeutic Peptide Design: Application to Amylin Receptor Agonists

Human amylin (hAmylin) regulates satiety and glucose metabolism but also forms islet amyloid in type 2 diabetes, contributing to Beta-cell dysfunction and death. hAmylin receptor agonists are therapeutically important for the treatment of diabetes and obesity, but
hAmylin’s high amyloidogenicity and the toxicity associated with its aggregates preclude its direct clinical use. hAmylin receptor agonists have been developed, but suffer from limited solubility, particularly at or near neutral pH, complicating their co-formulated with insulin.
We demonstrate that analysis of amylin sequences from extant species that do not develop islet amyloid provides key insights into the design of next-generation human amylin receptor agonists with improved properties that are soluble, non-amyloidogenic, and non-toxic, while
incorporating a minimal number of substitutions. This evolutionary analysis, combined with mechanistic biophysical studies, also reveals key determinants of amyloidogenicity. Together, these findings provide insight into both the rational design of soluble, non-toxic amylin
receptor agonists and the evolutionary determinants of amylin amyloidogenicity.