Design, synthesis, and stability evaluation of semaglutide-derived lactam-stapled peptide scaffolds for GLP-1R targeting

Semaglutide-derived peptide scaffolds with lactam stapling and bulky aromatic amino-acid substitutions were designed and tested for stability. Of 108 designed candidates, 35 were synthesised; most showed improved stability in serum and against proteases compared with semaglutide, with three analogues standing out. The work provides a route to stabilised semaglutide-like peptides for future GLP-1R research, but does not test their functional effects.

Journal article — Computational design and stability testing study. Sample size: 35 synthesised stapled peptides (108 designed). Interventions: lactam-stapled semaglutide-derived peptide scaffolds; bulky aromatic non-natural amino acid substitution.

Of 108 stapled candidates designed, 35 peptides were synthesised and characterised. Most stapled analogues showed improved serum and proteolytic stability relative to semaglutide. The analogues 11CP-17B, 11CP-17N, and 11CP-19N had the most favourable stability profiles. Molecular dynamics simulations and MM-GBSA analysis predicted receptor-compatible poses and favourable interaction patterns for these representative analogues.

This paper offers semaglutide-focused researchers a rational strategy for constructing rigidified, lactam-stapled scaffolds derived from semaglutide's GLP-1R-engaging segment. It demonstrates improved in vitro stability and computational receptor compatibility for selected analogues, but it does not establish receptor activation, potency, safety, or therapeutic utility.

Key findings

A total of 108 stapled peptide candidates were designed, and 35 were synthesised and characterised.
Most stapled analogues had improved serum and proteolytic stability relative to semaglutide.
The analogues 11CP-17B, 11CP-17N, and 11CP-19N showed the most favourable stability profiles.
Molecular dynamics simulations and MM-GBSA analysis indicated receptor-compatible poses and favourable predicted interaction patterns for these representative analogues.

Limitations

No functional receptor activation, potency, or in vivo efficacy data are reported.
Stability was assessed in vitro and computationally, so pharmacokinetic behaviour in living systems remains unknown.
Only 35 of the 108 designed candidates were synthesised, so the full design space was not experimentally tested.
No clinical or human evidence is provided.

The record

Journal: Journal of enzyme inhibition and medicinal chemistry 41(1): 2714331
Published: 2026-08-11
PMID: 42578506 — DOI: 10.1080/14756366.2026.2714331
MeSH terms: Animals, Humans, Lactams, Peptides, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Drug Design, Glucagon-Like Peptides, Molecular Dynamics Simulation, Glucagon-Like Peptide-1 Receptor, Semaglutide
Author countries: China

Peptide profiles: Semaglutide.

All indexed evidence: Semaglutide trials & papers.