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© Research
Publication : bioRxiv

A novel computational method for head-to-tail peptide cyclization: application to urotensin II

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in bioRxiv - 05 Jan 2022

Yasaman Karami, Samuel Murail, Julien Giribaldi, Benjamin Lefranc, Jérôme Leprince, Sjoerd J. de Vries, Pierre Tufféry

Link to DOI – https://doi.org/10.1101/2022.01.05.475045

bioRxiv 2022.01.05.475045; doi: https://doi.org/10.1101/2022.01.05.475045

Peptides have recently re-gained interest as therapeutic candidates but their development remains confronted with several limitations including low bioavailability. Backbone head-to-tail cyclization is one effective strategy of peptide-based drug design to stabilize the conformation of bioactive peptides while preserving peptide properties in terms of low toxicity, binding affinity, target selectivity and preventing enzymatic degradation. However, very little is known about the sequence-structure relationship requirements of designing linkers for peptide cyclization in a rational manner. Recently, we have shown that large scale data-mining of available protein structures can lead to the precise identification of protein loop conformations, even from remote structural classes. Here, we transpose this approach to head-to-tail peptide cyclization. Firstly we show that given a linker sequence and the conformation of the linear peptide, it is possible to accurately predict the cyclized peptide conformation improving by over 1 Å over pre-existing protocols. Secondly, and more importantly, we show that is is possible to elaborate on the information inferred from protein structures to propose effective candidate linker sequences constrained by length and amino acid composition, providing the first framework for the rational peptide head-to-tail cyclization. As functional validation, we apply it to the design of a head-to-tail cyclized derivative of urotensin II, an 11-residue long peptide which exerts a broad array of biologic activities, making its cognate receptor a valuable and innovative therapeutic or diagnostic target. We propose a three amino acid candidate linker, leading to the first synthesized 14-residue long cyclic UII analogue with excellent retention of in vitro activity.

https://www.biorxiv.org/content/10.1101/2022.01.05.475045v1.abstract