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

doi:10.3390/molecules25040922

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

University of Kent
University of Coimbra

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

14 Downloads (Pure)

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. View Full-Text

Original language	English
Article number	922
Number of pages	11
Journal	Molecules
Volume	25
Issue number	4
DOIs	https://doi.org/10.3390/molecules25040922 https://doi.org/10.3390/molecules25040922
Publication status	Published - 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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cyclic Peptides
NMR Structure
Drug Design
Protein‐Protein Interaction
NMR structure
Protein-protein interaction
Cyclic peptides
Drug design
drug design
RECEPTOR
NECROSIS-FACTOR-ALPHA
cyclic peptides
PEPTIDOMIMETICS
INHIBITION
LIGANDS
protein-protein interaction
INFLIXIMAB
EXPRESSION
BINDING

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10.3390/molecules25040922Licence: CC BY
10.3390/molecules25040922

Idress_etal_molecules_Structure_Based_VOR
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited https://creativecommons.org/licenses/by/4.0/
Final published version, 1.74 MBLicence: CC BY

https://www.mdpi.com/1420-3049/25/4/922

Cite this

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

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{\textendash}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 ",

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AU - Houssen, Wael E

N1 - 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.

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N2 - 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

AB - 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

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KW - INHIBITION

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SN - 1420-3049

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IS - 4

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ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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