Structure‐based design, synthesis and bioactivity of a new anti‐TNFα cyclopeptide

Mohannad Idress, Bruce F. Milne, Gary S. Thompson, Laurent Trembleau, Marcel Jaspars, Wael E Houssen* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
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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
Original languageEnglish
Article number922
Number of pages11
Issue number4
Publication statusPublished - 19 Feb 2020

Bibliographical note

This project was supported by grants from the University of Aberdeen (Elphinstone PhD scholarship, M.I.), ERC (No. 339367, M.J.), EPSRC fellowship (EP/S027246/1, W.E.H.). B.F.M. funded by the Portuguese Fundação para a Ciência e a Tecnologia (projects CENTRO-01- 0145-FEDER-000014, 2017-2020 and POCI-01-0145-FEDER-032229) and the Donostia International Physics Centre (San Sebastián, Spain). The Coimbra Chemistry Centre is supported by the Fundação para a Ciência e a Tecnologia, through the Project PEstOE/QUI/UI0313/2014 and POCI-01-0145-FEDER-007630.


  • Cyclic Peptides
  • NMR Structure
  • Drug Design
  • Protein‐Protein Interaction
  • NMR structure
  • Protein-protein interaction
  • Cyclic peptides
  • Drug design
  • drug design
  • cyclic peptides
  • protein-protein interaction


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