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Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes

[Image: see text] The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential i...

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Autores principales: Bell, Andrew S., Yu, Zhiyong, Hutton, Jennie A., Wright, Megan H., Brannigan, James A., Paape, Daniel, Roberts, Shirley M., Sutherell, Charlotte L., Ritzefeld, Markus, Wilkinson, Anthony J., Smith, Deborah F., Leatherbarrow, Robin J., Tate, Edward W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383931/
https://www.ncbi.nlm.nih.gov/pubmed/32575985
http://dx.doi.org/10.1021/acs.jmedchem.0c00570
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author Bell, Andrew S.
Yu, Zhiyong
Hutton, Jennie A.
Wright, Megan H.
Brannigan, James A.
Paape, Daniel
Roberts, Shirley M.
Sutherell, Charlotte L.
Ritzefeld, Markus
Wilkinson, Anthony J.
Smith, Deborah F.
Leatherbarrow, Robin J.
Tate, Edward W.
author_facet Bell, Andrew S.
Yu, Zhiyong
Hutton, Jennie A.
Wright, Megan H.
Brannigan, James A.
Paape, Daniel
Roberts, Shirley M.
Sutherell, Charlotte L.
Ritzefeld, Markus
Wilkinson, Anthony J.
Smith, Deborah F.
Leatherbarrow, Robin J.
Tate, Edward W.
author_sort Bell, Andrew S.
collection PubMed
description [Image: see text] The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure–activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.
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spelling pubmed-73839312020-07-28 Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes Bell, Andrew S. Yu, Zhiyong Hutton, Jennie A. Wright, Megan H. Brannigan, James A. Paape, Daniel Roberts, Shirley M. Sutherell, Charlotte L. Ritzefeld, Markus Wilkinson, Anthony J. Smith, Deborah F. Leatherbarrow, Robin J. Tate, Edward W. J Med Chem [Image: see text] The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with millions of cases worldwide. Current therapeutic approaches are limited by toxicity, resistance, and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising anti-leishmanial target. Here we describe a comprehensive structure–activity relationship (SAR) study of a thienopyrimidine series previously identified in a high-throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay, we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against Leishmania donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs. American Chemical Society 2020-06-24 2020-07-23 /pmc/articles/PMC7383931/ /pubmed/32575985 http://dx.doi.org/10.1021/acs.jmedchem.0c00570 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Bell, Andrew S.
Yu, Zhiyong
Hutton, Jennie A.
Wright, Megan H.
Brannigan, James A.
Paape, Daniel
Roberts, Shirley M.
Sutherell, Charlotte L.
Ritzefeld, Markus
Wilkinson, Anthony J.
Smith, Deborah F.
Leatherbarrow, Robin J.
Tate, Edward W.
Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
title Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
title_full Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
title_fullStr Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
title_full_unstemmed Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
title_short Novel Thienopyrimidine Inhibitors of Leishmania N-Myristoyltransferase with On-Target Activity in Intracellular Amastigotes
title_sort novel thienopyrimidine inhibitors of leishmania n-myristoyltransferase with on-target activity in intracellular amastigotes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383931/
https://www.ncbi.nlm.nih.gov/pubmed/32575985
http://dx.doi.org/10.1021/acs.jmedchem.0c00570
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