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Increasing the bioactive space of peptide macrocycles by thioamide substitution

Verma, Hitesh and Khatri, Bhavesh and Chakraborti, Sohini and Chatterjee, Jayanta (2018) Increasing the bioactive space of peptide macrocycles by thioamide substitution. In: CHEMICAL SCIENCE, 9 (9). pp. 2443-2451.

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Official URL: http://dx.doi.org/ 10.1039/c7sc04671e


We show that substituting a single atom, O to S (amide to thioamide), in a peptide bond results in global restriction of the conformational flexibility in peptide macrocycles with minimal perturbation of the parent conformation. The van der Waals interactions between the C=S group and the surrounding atoms are the major driving force in inducing the conformational restriction, resulting in well-defined structures of these cyclic peptides with static 3-D presentation of the pharmacophores. Utilizing this property of thioamides, we report the development of a superactive antagonist of pro-angiogenic alpha nu beta 3, alpha nu beta 5 and alpha 5 beta 1 integrins, which are responsible for cancer cell proliferation and survival. Using simple thio-scanning and spatial screening of a non-efficacious and conformationally flexible cyclic peptide, we could achieve a more than 105 fold enhancement in its efficacy in cellulo via a single O to S substitution. The developed peptide shows better efficacy in inhibiting the pro-angiogenic integrins than the drug candidate cilengitide, with a significantly enhanced serum half-life of 36 h compared to that of cilengitide (12 h). The long shelf-life, absence of non-specific toxicity and resistance to degradation of the thioamidated macrocyclic peptides in human serum suggest the promise of thioamides in markedly improving the affinity, efficacy and pharmacology of peptide macrocycles.

Item Type: Journal Article
Additional Information: Copy right for this article belong to ROYAL SOC CHEMISTRY, THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND
Department/Centre: Division of Biological Sciences > Molecular Biophysics Unit
Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Depositing User: Id for Latest eprints
Date Deposited: 17 May 2018 18:27
Last Modified: 17 May 2018 18:27
URI: http://eprints.iisc.ac.in/id/eprint/59888

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