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In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

[Image: see text] A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure–activity relationships of a recently disc...

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Autores principales: Ottavi, Samantha, Scarry, Sarah M., Mosior, John, Ling, Yan, Roberts, Julia, Singh, Amrita, Zhang, David, Goullieux, Laurent, Roubert, Christine, Bacqué, Eric, Lagiakos, H. Rachel, Vendome, Jeremie, Moraca, Francesca, Li, Kelin, Perkowski, Andrew J., Ramesh, Remya, Bowler, Matthew M., Tracy, William, Feher, Victoria A., Sacchettini, James C., Gold, Ben S., Nathan, Carl F., Aubé, Jeffrey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842310/
https://www.ncbi.nlm.nih.gov/pubmed/35044775
http://dx.doi.org/10.1021/acs.jmedchem.1c01565
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author Ottavi, Samantha
Scarry, Sarah M.
Mosior, John
Ling, Yan
Roberts, Julia
Singh, Amrita
Zhang, David
Goullieux, Laurent
Roubert, Christine
Bacqué, Eric
Lagiakos, H. Rachel
Vendome, Jeremie
Moraca, Francesca
Li, Kelin
Perkowski, Andrew J.
Ramesh, Remya
Bowler, Matthew M.
Tracy, William
Feher, Victoria A.
Sacchettini, James C.
Gold, Ben S.
Nathan, Carl F.
Aubé, Jeffrey
author_facet Ottavi, Samantha
Scarry, Sarah M.
Mosior, John
Ling, Yan
Roberts, Julia
Singh, Amrita
Zhang, David
Goullieux, Laurent
Roubert, Christine
Bacqué, Eric
Lagiakos, H. Rachel
Vendome, Jeremie
Moraca, Francesca
Li, Kelin
Perkowski, Andrew J.
Ramesh, Remya
Bowler, Matthew M.
Tracy, William
Feher, Victoria A.
Sacchettini, James C.
Gold, Ben S.
Nathan, Carl F.
Aubé, Jeffrey
author_sort Ottavi, Samantha
collection PubMed
description [Image: see text] A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure–activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca(v)1.2 and Na(v)1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide).
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spelling pubmed-88423102022-02-15 In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas Ottavi, Samantha Scarry, Sarah M. Mosior, John Ling, Yan Roberts, Julia Singh, Amrita Zhang, David Goullieux, Laurent Roubert, Christine Bacqué, Eric Lagiakos, H. Rachel Vendome, Jeremie Moraca, Francesca Li, Kelin Perkowski, Andrew J. Ramesh, Remya Bowler, Matthew M. Tracy, William Feher, Victoria A. Sacchettini, James C. Gold, Ben S. Nathan, Carl F. Aubé, Jeffrey J Med Chem [Image: see text] A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure–activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca(v)1.2 and Na(v)1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide). American Chemical Society 2022-01-19 2022-02-10 /pmc/articles/PMC8842310/ /pubmed/35044775 http://dx.doi.org/10.1021/acs.jmedchem.1c01565 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Ottavi, Samantha
Scarry, Sarah M.
Mosior, John
Ling, Yan
Roberts, Julia
Singh, Amrita
Zhang, David
Goullieux, Laurent
Roubert, Christine
Bacqué, Eric
Lagiakos, H. Rachel
Vendome, Jeremie
Moraca, Francesca
Li, Kelin
Perkowski, Andrew J.
Ramesh, Remya
Bowler, Matthew M.
Tracy, William
Feher, Victoria A.
Sacchettini, James C.
Gold, Ben S.
Nathan, Carl F.
Aubé, Jeffrey
In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas
title In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas
title_full In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas
title_fullStr In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas
title_full_unstemmed In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas
title_short In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas
title_sort in vitro and in vivo inhibition of the mycobacterium tuberculosis phosphopantetheinyl transferase pptt by amidinoureas
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8842310/
https://www.ncbi.nlm.nih.gov/pubmed/35044775
http://dx.doi.org/10.1021/acs.jmedchem.1c01565
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