A rationally designed 18-amino acid peptide with potential as GLP-1 receptor agonist.
This study describes the computational design and preliminary laboratory characterization of SR18, a rationally engineered 18-amino acid peptide candidate intended to act as a GLP-1 receptor (GLP-1R) agonist for potential use in Type 2 diabetes (T2DM). The researchers used in silico methods—including molecular docking and 1-microsecond molecular dynamics (MD) simulations—to design SR18 to be resistant to DPP-4 cleavage and to retain key amino acids that interact with GLP-1R, similar to endogenous GLP-1 and approved drugs like Semaglutide and Liraglutide. In laboratory experiments, circular dichroism confirmed that synthesized SR18 adopts a stable α-helical conformation across various solvent conditions. Dynamic light scattering, cytotoxicity, and hemolytic assays suggested acceptable basic pharmaceutical and safety properties for a lead peptide candidate. Computational analyses indicated that SR18 may bind GLP-1R with comparable or favorable affinity relative to GLP-1 and Semaglutide. Limitations include the absence of any cell-based receptor activation assays, animal studies, or human data; the evidence remains entirely in silico and in vitro. No conclusions about clinical efficacy can be drawn at this stage.
Why this grade: All findings are derived from computational modeling, molecular dynamics simulations, and basic in vitro characterization assays, with no animal or human data presented.
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.
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