Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783563521976434688 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7383931 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bellandrews novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT yuzhiyong novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT huttonjenniea novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT wrightmeganh novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT branniganjamesa novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT paapedaniel novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT robertsshirleym novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT sutherellcharlottel novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT ritzefeldmarkus novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT wilkinsonanthonyj novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT smithdeborahf novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT leatherbarrowrobinj novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes AT tateedwardw novelthienopyrimidineinhibitorsofleishmanianmyristoyltransferasewithontargetactivityinintracellularamastigotes |