Brannigan, James A. and Wilkinson, Anthony J. orcid.org/0000-0003-4577-9479 (2021) Drug discovery in leishmaniasis using protein lipidation as a target. Biophysical Reviews. 1139–1146. ISSN 1867-2450
Abstract
The leishmaniases are infectious diseases caused by a number of species of obligate intracellular protozoa of the genus Leishmania with disease manifesting as cutaneous, mucocutaneous and visceral forms. Despite being endemic in more than 80 countries and its being the cause of high morbidity and mortality, leishmaniasis remains a neglected tropical disease. Chemotherapy is the frontline treatment, but drugs in current use suffer from toxic side effects, difficulties in administration and extended treatment times — moreover, resistance is emerging. New anti-leishmanial drugs are a recognised international priority. Here, we review investigations into N-myristoyltransferase (NMT) as a potential drug target. NMT catalyses the co-translational transfer of a C14 fatty acid from myristoyl-CoA onto the N-terminal glycine residue of a significant subset of proteins in eukaryotic cells. This covalent modification influences the stability and interactions of substrate proteins with lipids and partner proteins. Structure-guided development of new lead compounds emerging from high-throughput screening campaigns targeting Leishmania donovani NMT has led to the discovery of potent inhibitors which have been used to gain insights into the role of protein myristoylation in these parasites and to validate NMT as a drug target.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Funding Information: This work was funded by earlier grants from the MRC and the Wellcome Trust. Our current Leishmania work is supported as part of an RCUK GCRF grant (MR/P027989/1) ‘A Global Network for Neglected Tropical Diseases’. Publisher Copyright: © 2021, The Author(s). |
Keywords: | Leishmaniasis inhibitor discovery,N-myristoyltransferase,Neglected tropical disease,Protein structure |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 05 Jan 2022 13:20 |
Last Modified: | 17 Dec 2024 00:21 |
Published Version: | https://doi.org/10.1007/s12551-021-00855-0 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1007/s12551-021-00855-0 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:182108 |
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Description: Drug discovery in leishmaniasis using protein lipidation as a target
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