Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs.
Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection agai...
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ftdoajarticles:oai:doaj.org/article:f9cdeabdf89e4f4f804ccc4da454aa0f 2023-05-15T15:10:44+02:00 Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. Andrew S Bell James E Mills Gareth P Williams James A Brannigan Anthony J Wilkinson Tanya Parkinson Robin J Leatherbarrow Edward W Tate Anthony A Holder Deborah F Smith 2012-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0001625 https://doaj.org/article/f9cdeabdf89e4f4f804ccc4da454aa0f EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3335879?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001625 https://doaj.org/article/f9cdeabdf89e4f4f804ccc4da454aa0f PLoS Neglected Tropical Diseases, Vol 6, Iss 4, p e1625 (2012) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2012 ftdoajarticles https://doi.org/10.1371/journal.pntd.0001625 2022-12-30T22:30:04Z Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 6 4 e1625 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Andrew S Bell James E Mills Gareth P Williams James A Brannigan Anthony J Wilkinson Tanya Parkinson Robin J Leatherbarrow Edward W Tate Anthony A Holder Deborah F Smith Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases. |
format |
Article in Journal/Newspaper |
author |
Andrew S Bell James E Mills Gareth P Williams James A Brannigan Anthony J Wilkinson Tanya Parkinson Robin J Leatherbarrow Edward W Tate Anthony A Holder Deborah F Smith |
author_facet |
Andrew S Bell James E Mills Gareth P Williams James A Brannigan Anthony J Wilkinson Tanya Parkinson Robin J Leatherbarrow Edward W Tate Anthony A Holder Deborah F Smith |
author_sort |
Andrew S Bell |
title |
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
title_short |
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
title_full |
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
title_fullStr |
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
title_full_unstemmed |
Selective inhibitors of protozoan protein N-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
title_sort |
selective inhibitors of protozoan protein n-myristoyltransferases as starting points for tropical disease medicinal chemistry programs. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doi.org/10.1371/journal.pntd.0001625 https://doaj.org/article/f9cdeabdf89e4f4f804ccc4da454aa0f |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 6, Iss 4, p e1625 (2012) |
op_relation |
http://europepmc.org/articles/PMC3335879?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001625 https://doaj.org/article/f9cdeabdf89e4f4f804ccc4da454aa0f |
op_doi |
https://doi.org/10.1371/journal.pntd.0001625 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
6 |
container_issue |
4 |
container_start_page |
e1625 |
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1766341706898210816 |