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Open AccessArticle

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

Institute of Medical Sciences, University of Aberdeen, Ashgrove Road West, Aberdeen AB25 2ZD, UK
Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK
CFisUC, Department of Physics, University of Coimbra, Rua Larga, 3004-516 Coimbra, Portugal
Wellcome Trust Biomolecular NMR Facility, School of Biosciences, University of Kent, Canterbury, Kent, England CT2 7NZ, UK
Author to whom correspondence should be addressed.
Molecules 2020, 25(4), 922;
Received: 30 January 2020 / Revised: 9 February 2020 / Accepted: 14 February 2020 / Published: 19 February 2020
(This article belongs to the Special Issue Bioactive Peptides—From Therapy to Nutrition)
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. View Full-Text
Keywords: cyclic peptides; NMR structure; drug design; protein–protein interaction cyclic peptides; NMR structure; drug design; protein–protein interaction
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MDPI and ACS Style

Idress, M.; Milne, B.F.; Thompson, G.S.; Trembleau, L.; Jaspars, M.; Houssen, W.E. Structure-Based Design, Synthesis and Bioactivity of a New Anti-TNFα Cyclopeptide. Molecules 2020, 25, 922.

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