A rationally designed 18-amino acid peptide with potential as GLP-1 receptor agonist.

Introduction: Diabetes mellitus (DM) is a multifaceted disease etiologically characterised by dysregulation in glucose homeostasis. The World Health Organization (WHO) global report indicates that over 90% of DM cases are classified as Type 2 DM (T2DM), which is clinically characterized by chronic hyperglycemia. This systemic condition arises predominantly due to the interplay of two key components: (a) compromised insulin production by the pancreatic β-cells, and (b) the failure of insulin-sensitive tissues to react to insulin. Notably, it is well established that glucagon-like peptide-1 (GLP-1), an incretin hormone of the glucagon superfamily, contributes to glucose-dependent pancreatic β-cell insulin secretion. The insulinotropic impacts of secreted GLP-1 are facilitated by its interaction with GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR). However, GLP-1 is proteolytically cleaved by dipeptidyl peptidase 4 (DPP-4), resulting in a plasma half-life of ∼2 minutes, which limits its therapeutic efficacy in patients with T2DM. Therefore, the exogenous administration of DPP-4-resistant GLP-1R agonists (GLP-1RAs) has proven to be a successful therapeutic strategy for managing T2DM. Notably, the currently marketed GLP-1RAs, such as Semaglutide, Liraglutide, and Lixisenatide, are long-chain GLP-1 mimetic peptides, ranging in length from 33 to 39 amino acids. Methods: In this context, the computational design and in silico evaluation of a DPP-4- resistant, potent designer helical peptide agonist (SR18; ≤18 aa) of the GLP-1R, comprised of both coded and non-coded amino acids, are described in the current study. The basic pharmacological activity of the designer peptide, SR18 was evaluated through circular dichroism, dynamic light scattering, proteolysis, cytotoxicity and hemolytic experiments. Results and discussions: SR18 preserves several amino acids necessary for effective interactions with the GLP-1R, similar to those found in GLP-1, Liraglutide, and Semaglutide. Interestingly, the binding of SR18 also mimics the binding of small-molecule agonists of GLP-1R. Preliminary experimental studies confirm that synthetically prepared SR18 maintains an ordered, α-helical conformation under various solvent conditions and possesses the basic pharmaceutical properties desired of a potent lead peptide. Furthermore, compared with GLP-1 and Semaglutide SR18 exhibits stable interactions with GLP-1R over 1 μs of molecular dynamics (MD) simulations, with appreciable binding affinity and energy, supporting its viability as a potential alternative to the current long-chain GLP-1R peptide agonists.