Peptide Engineering Strategies for AT1R: Structure-Based Analysis of Angiotensin II Analogues

The angiotensin II type 1 receptor (AT1R) is a Class A G protein-coupled receptor activated by the endogenous octapeptide angiotensin II (Ang II) and plays a central role in blood-pressure regulation, fluid homeostasis and cardiovascular signalling. The well-characterised peptide–receptor system provides a useful model for investigating how defined peptide modifications influence GPCR recognition.

In this study, Ang II was used as a reference scaffold for the structure-based design of peptide analogues with altered conformational and physicochemical properties. The investigated strategies included head-to-tail cyclisation, introduction of D-amino-acid residues and N-terminal truncation. Molecular docking with AT1R was used to compare the resulting binding poses, receptor-contact patterns and the preservation or redistribution of key peptide–receptor interactions.

The head-to-tail cyclic analogue showed the most favourable docking performance compared with native Ang II. It retained favourable AT1R interactions while displaying a modified hydrogen-bond and hydrophobic contact pattern, suggesting that cyclisation can influence peptide–receptor recognition

The comparative analysis is intended to identify which peptide-engineering strategies preserve favourable AT1R recognition while modifying peptide conformation. These results may provide a basis for further molecular dynamics studies and for the rational design of conformationally controlled peptide ligands targeting AT1R.

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