Rationally designed small peptides targeting DPP-4: Identification of potent anti-diabetic agents

  • Bioorg Chem. 2025 Aug:163:108781. doi: 10.1016/j.bioorg.2025.108781.
Sombir Jaglan  1 ,  Palwinder Singh  2 ,  Sheetal Vermani  1 ,  Varinder Kaur  1 ,  Sarabjit Kaur  3 ,  Abdulkadir Abdu  3
Affiliations
  • 1. Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India.
  • 2. Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India. Electronic address: [email protected].
  • 3. Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar 143005, India.
PMID: 40700924 DOI: 10.1016/j.bioorg.2025.108781
Abstract

DPP-4 inhibition is a pioneering strategy to subdue type 2 diabetes. In this context, we designed and synthesized small peptide-based DPP-4 inhibitors. Eighteen peptides were synthesized, and their inhibition activity was determined. Compound 8 emerged as the most potent DPP-4 Inhibitor (IC50 0.12 nM) with desirable drug likeness properties including solubility, plasma stability, kinetic study, and ADME properties. The in vivo anti-diabetic potency was evaluated in a diabetic model of STZ/NA-induced Wistar rats. Compound 8 not only lined up glucose levels to normal but also improved serum's lipid parameters, liver Enzymes, and renal parameters at medium (20 mg/kg) and high doses (40 mg/kg). Further histopathological analysis of kidney and pancreas tissue shows its curative effect. Compound 8 exhibits selectivity for DPP-4 as binding energy computed by post-dynamic analysis MM-GBSA for compound 8 complex in DPP-4 is almost twofold as of DPP-8 and DPP-9.

Keywords
Dipeptidyl peptidase-4; Drug-likeness; Glucose; Histopathology; Molecular modelling; Peptides; Type 2 diabetes mellitus.
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