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Increasing the bioactive space of peptide macrocycles by thioamide substitution

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Abstract

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[double bond, length as m-dash]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 αvβ3, αvβ5 and α5β1 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.

Graphical abstract: Increasing the bioactive space of peptide macrocycles by thioamide substitution

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Publication details

The article was received on 28 Oct 2017, accepted on 19 Jan 2018 and first published on 22 Jan 2018


Article type: Edge Article
DOI: 10.1039/C7SC04671E
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY license
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    Increasing the bioactive space of peptide macrocycles by thioamide substitution

    H. Verma, B. Khatri, S. Chakraborti and J. Chatterjee, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C7SC04671E

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