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Structure-Based Design, Synthesis and Bioactivity of a New Anti-TNFα Cyclopeptide

Idress, Mohannad, Milne, Bruce F., Thompson, Gary S., Trembleau, Laurent, Jaspars, Marcel, Houssen, Wael E. (2020) Structure-Based Design, Synthesis and Bioactivity of a New Anti-TNFα Cyclopeptide. Molecules, 25 (4). p. 922. ISSN 1420-3049. (doi:10.3390/molecules25040922) (KAR id:80542)

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https://doi.org/10.3390/molecules25040922

Abstract

As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein–protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide.

Item Type: Article
DOI/Identification number: 10.3390/molecules25040922
Uncontrolled keywords: cyclic peptides; NMR structure; drug design; protein–protein interaction
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Gary Thompson
Date Deposited: 18 Mar 2020 16:37 UTC
Last Modified: 18 Mar 2020 16:38 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/80542 (The current URI for this page, for reference purposes)
Thompson, Gary S.: https://orcid.org/0000-0001-9399-7636
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