Rationally Designed 18-Amino Acid Peptide SR18 Shows Potential as DPP-4-Resistant GLP-1 Receptor Agonist

Type 2 Diabetes Mellitus (T2DM), characterized by chronic hyperglycemia, stems from impaired pancreatic β-cell insulin production and insulin resistance. Glucagon-like peptide-1 (GLP-1), an incretin hormone, stimulates glucose-dependent insulin secretion via the GLP-1 receptor (GLP-1R). However, endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), limiting its therapeutic utility. Current GLP-1R agonists (GLP-1RAs) like Semaglutide are long-chain peptides (33-39 amino acids), necessitating the development of shorter, more stable, and potent alternatives to improve patient compliance and reduce potential side effects.

Researchers computationally designed and in silico evaluated SR18, a novel 18-amino acid helical peptide, as a potential DPP-4-resistant GLP-1R agonist. The design incorporated both coded and non-coded amino acids to optimize its properties. Following in silico validation, the basic pharmacological activity of SR18 was assessed in vitro using several assays. These included circular dichroism to evaluate secondary structure, dynamic light scattering for aggregation state, proteolysis experiments to determine DPP-4 resistance, and cytotoxicity and hemolytic assays to assess its safety profile in cellular models.

The computational design of SR18 successfully yielded an 18-amino acid peptide intended to mimic GLP-1's interaction with its receptor while conferring resistance to DPP-4 degradation. The in silico evaluation indicated that SR18 retains critical amino acid residues essential for effective binding to the GLP-1R, mirroring those found in native GLP-1 and established GLP-1RAs like Liraglutide. Subsequent in vitro experiments confirmed the peptide's structural integrity and stability. While specific quantitative data on agonistic activity (e.g., EC50 values) or direct comparisons to existing GLP-1RAs were not detailed in the abstract, the comprehensive in vitro assessment of its basic pharmacological properties, including proteolysis (for DPP-4 resistance), cytotoxicity, and hemolytic activity, suggests a promising initial profile. These evaluations are foundational steps in validating the peptide's potential as a therapeutic candidate. > The rationally designed SR18 peptide, at just 18 amino acids, was shown to preserve key GLP-1R interaction sites and was evaluated for DPP-4 resistance and safety in vitro.