Supramolecular Engineering of Ultra-Long-Lasting GLP-1 Depots

PROJECT SUMMARY: The treatment of diabetes and obesity has seen an inflection in recent years with the approval of once-weekly glucagon-like peptide 1 receptor agonists (GLP1-RAs), which offer support in glucose metabolism for a week following a single injection. In spite of more convenient once-weekly self-administration, improving over the daily or twice-daily injection schedules of earlier agents in this class, the use of these newer GLP1-RAs still suffers from sub-optimal therapeutic persistence due to a combination of side-effects and poor compliance with self-administration schedules. The creation of GLP1-RA therapies with multi-month duration of function would circumvent both challenges. First, controlled release GLP1RA depots are known from clinical evidence to reduce side-effects compared to administration of the free peptides. Second, a multi-month dosing schedule would better correspond to the schedule of routine clinical touch-points with physicians or pharmacists and thereby avoid the need for self-administration entirely. Our preliminary work leveraged the identity of GLP1- RAs as synthetic peptides amendable to synthesis by standard solid-phase methods, further engineering these through facile side-chain modifications to present motifs that promote nanofibrillar self-assembly and hydrogelation. The resulting injectable self-assembling GLP1-RAs offered long-lasting serum concentrations and improved therapeutic outcomes when assessed in a rat model of type 2 diabetes. This proposal will seek to build on this initial concept by further tuning the engineered self-assembly motif to enable robust single- component nanofiber assembly and hydrogelation while ensuring potent receptor signaling and physicochemical stability. The enhanced designs will then be assessed as injectable depots for their ability to control blood glucose and weight gain in a model of type 2 diabetes, along with a detailed assessment of their biocompatibility in the context of subcutaneous application. Finally, the modularity of this approach will be assessed by integrating a next-generation therapeutic in this class that functions through simultaneous signaling of three separate receptors involved in metabolic regulation. Through these studies, our innovative concept to develop a long-lasting GLP1-RA depot by direct self-assembly of the therapeutic agent will be further optimized and assessed for its potential in combating the ongoing diabetes and obesity epidemics. Specifically, this approach conceives of new self-assembling therapeutic peptide depots that offer controlled release to reduce dosing frequency and stable serum concentrations to better mitigate side-effects.