Zhang, B, Wang, Y, Lin, C et al. (7 more authors) (2021) Targeting the transmembrane domain 5 of latent membrane protein 1 using small molecule modulators. European Journal of Medicinal Chemistry, 214. 113210. ISSN 0223-5234
Abstract
Protein-protein interactions (PPIs) play a critical role in living cells and represent promising targets for the drug discovery and life sciences communities. However, lateral transmembrane PPIs are difficult targets for small-molecule inhibitor development given less structural information is known and fewer ligand discovery methods have been explored compared to soluble proteins. In this study, the interactions of the transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) of Epstein-Barr virus (EBV) were disrupted by pentamidine derivatives to curb the committed step of EBV infection. A pentamidine derivative 2 with a 7-atom di-amide linker had the best activity whilst switching the amide regiochemistry in the linker influenced membrane permeability and abolished anti TMD-5 activity. Molecular dynamics simulations were performed to understand the interaction between pentamidine derivatives and TMD-5, and to rationalise the observed structure-activity relationships. This study explicitly demonstrated that the interaction of small molecule with lipid should be considered alongside interaction with the protein target when designing small molecules targeting the PPIs of TMDs. In all, this study provides proof of concept for the rational design of small molecules targeting transmembrane PPIs.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 Elsevier Masson SAS. All rights reserved. This is an author produced version of an published in . Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Protein-protein interactions; Pentamidine analogues |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Feb 2021 14:40 |
Last Modified: | 27 Jan 2022 01:38 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.ejmech.2021.113210 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:170915 |
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