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Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome

Mycobacterium tuberculosis is responsible for the greatest number of deaths worldwide due to a bacterial agent. We recently identified bortezomib (Velcade; compound 1) as a promising antituberculosis (anti-TB) compound. We showed that compound 1 inhibits the mycobacterial caseinolytic proteases P1 a...

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Autores principales: Moreira, Wilfried, Santhanakrishnan, Sridhar, Ngan, Grace J. Y., Low, Choon Bing, Sangthongpitag, Kanda, Poulsen, Anders, Dymock, Brian W., Dick, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404560/
https://www.ncbi.nlm.nih.gov/pubmed/28193668
http://dx.doi.org/10.1128/AAC.02307-16
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author Moreira, Wilfried
Santhanakrishnan, Sridhar
Ngan, Grace J. Y.
Low, Choon Bing
Sangthongpitag, Kanda
Poulsen, Anders
Dymock, Brian W.
Dick, Thomas
author_facet Moreira, Wilfried
Santhanakrishnan, Sridhar
Ngan, Grace J. Y.
Low, Choon Bing
Sangthongpitag, Kanda
Poulsen, Anders
Dymock, Brian W.
Dick, Thomas
author_sort Moreira, Wilfried
collection PubMed
description Mycobacterium tuberculosis is responsible for the greatest number of deaths worldwide due to a bacterial agent. We recently identified bortezomib (Velcade; compound 1) as a promising antituberculosis (anti-TB) compound. We showed that compound 1 inhibits the mycobacterial caseinolytic proteases P1 and P2 (ClpP1P2) and exhibits bactericidal activity, and we established compound 1 and ClpP1P2 as an attractive lead/target couple. However, compound 1 is a human-proteasome inhibitor currently approved for cancer therapy and, as such, exhibits significant toxicity. Selective inhibition of the bacterial protease over the human proteasome is desirable in order to maintain antibacterial activity while reducing toxicity. We made use of structural data in order to design a series of dipeptidyl-boronate derivatives of compound 1. We tested these derivatives for whole-cell ClpP1P2 and human-proteasome inhibition as well as bacterial-growth inhibition and identified compounds that were up to 100-fold-less active against the human proteasome but that retained ClpP1P2 and mycobacterial-growth inhibition as well as bactericidal potency. The lead compound, compound 58, had low micromolar ClpP1P2 and anti-M. tuberculosis activity, good aqueous solubility, no cytochrome P450 liabilities, moderate plasma protein binding, and low toxicity in two human liver cell lines, and despite high clearance in microsomes, this compound was only moderately cleared when administered intravenously or orally to mice. Higher-dose oral pharmacokinetics indicated good dose linearity. Furthermore, compound 58 was inhibitory to only 11% of a panel of 62 proteases. Our work suggests that selectivity over the human proteasome can be achieved with a drug-like template while retaining potency against ClpP1P2 and, crucially, anti-M. tuberculosis activity.
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spelling pubmed-54045602017-05-09 Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome Moreira, Wilfried Santhanakrishnan, Sridhar Ngan, Grace J. Y. Low, Choon Bing Sangthongpitag, Kanda Poulsen, Anders Dymock, Brian W. Dick, Thomas Antimicrob Agents Chemother Experimental Therapeutics Mycobacterium tuberculosis is responsible for the greatest number of deaths worldwide due to a bacterial agent. We recently identified bortezomib (Velcade; compound 1) as a promising antituberculosis (anti-TB) compound. We showed that compound 1 inhibits the mycobacterial caseinolytic proteases P1 and P2 (ClpP1P2) and exhibits bactericidal activity, and we established compound 1 and ClpP1P2 as an attractive lead/target couple. However, compound 1 is a human-proteasome inhibitor currently approved for cancer therapy and, as such, exhibits significant toxicity. Selective inhibition of the bacterial protease over the human proteasome is desirable in order to maintain antibacterial activity while reducing toxicity. We made use of structural data in order to design a series of dipeptidyl-boronate derivatives of compound 1. We tested these derivatives for whole-cell ClpP1P2 and human-proteasome inhibition as well as bacterial-growth inhibition and identified compounds that were up to 100-fold-less active against the human proteasome but that retained ClpP1P2 and mycobacterial-growth inhibition as well as bactericidal potency. The lead compound, compound 58, had low micromolar ClpP1P2 and anti-M. tuberculosis activity, good aqueous solubility, no cytochrome P450 liabilities, moderate plasma protein binding, and low toxicity in two human liver cell lines, and despite high clearance in microsomes, this compound was only moderately cleared when administered intravenously or orally to mice. Higher-dose oral pharmacokinetics indicated good dose linearity. Furthermore, compound 58 was inhibitory to only 11% of a panel of 62 proteases. Our work suggests that selectivity over the human proteasome can be achieved with a drug-like template while retaining potency against ClpP1P2 and, crucially, anti-M. tuberculosis activity. American Society for Microbiology 2017-04-24 /pmc/articles/PMC5404560/ /pubmed/28193668 http://dx.doi.org/10.1128/AAC.02307-16 Text en Copyright © 2017 Moreira et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Experimental Therapeutics
Moreira, Wilfried
Santhanakrishnan, Sridhar
Ngan, Grace J. Y.
Low, Choon Bing
Sangthongpitag, Kanda
Poulsen, Anders
Dymock, Brian W.
Dick, Thomas
Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
title Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
title_full Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
title_fullStr Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
title_full_unstemmed Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
title_short Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
title_sort towards selective mycobacterial clpp1p2 inhibitors with reduced activity against the human proteasome
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404560/
https://www.ncbi.nlm.nih.gov/pubmed/28193668
http://dx.doi.org/10.1128/AAC.02307-16
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