Please use this identifier to cite or link to this item:
https://doi.org/10.1128/AAC.02307-16
DC Field | Value | |
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dc.title | Towards selective mycobacterial ClpP1P2 inhibitors with reduced activity against the human proteasome | |
dc.contributor.author | Moreira, W | |
dc.contributor.author | Santhanakrishnan, S | |
dc.contributor.author | Ngan, G.J.Y | |
dc.contributor.author | Low, C.B | |
dc.contributor.author | Sangthongpitag, K | |
dc.contributor.author | Poulsen, A | |
dc.contributor.author | Dymock, B.W | |
dc.contributor.author | Dick, T | |
dc.date.accessioned | 2020-09-09T06:24:41Z | |
dc.date.available | 2020-09-09T06:24:41Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Moreira, W, Santhanakrishnan, S, Ngan, G.J.Y, Low, C.B, Sangthongpitag, K, Poulsen, A, Dymock, B.W, Dick, T (2017). Towards selective mycobacterial ClpP1P2 inhibitors with reduced activity against the human proteasome. Antimicrobial Agents and Chemotherapy 61 (5) : e02307. ScholarBank@NUS Repository. https://doi.org/10.1128/AAC.02307-16 | |
dc.identifier.issn | 0066-4804 | |
dc.identifier.uri | https://scholarbank.nus.edu.sg/handle/10635/175227 | |
dc.description.abstract | 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 mycobacterialgrowth 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. Higherdose 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. Copyright © 2017 American Society for Microbiology. All Rights Reserved. | |
dc.publisher | American Society for Microbiology | |
dc.source | Unpaywall 20200831 | |
dc.subject | 3 phenyl 1 [[2 (pyrazine 2 carboxamido) 3 (pyridin 2 yl)propanimido]propyl]boronic acid | |
dc.subject | boronic acid derivative | |
dc.subject | bortezomib | |
dc.subject | cytochrome P450 | |
dc.subject | proteasome inhibitor | |
dc.subject | proteinase inhibitor | |
dc.subject | unclassified drug | |
dc.subject | antiinfective agent | |
dc.subject | bacterial protein | |
dc.subject | bortezomib | |
dc.subject | ClpP2 protein, bacteria | |
dc.subject | endopeptidase Clp | |
dc.subject | proteasome inhibitor | |
dc.subject | serine proteinase | |
dc.subject | animal experiment | |
dc.subject | animal model | |
dc.subject | antibacterial activity | |
dc.subject | Article | |
dc.subject | bacterial growth | |
dc.subject | bactericidal activity | |
dc.subject | controlled study | |
dc.subject | drug solubility | |
dc.subject | enzyme inhibition | |
dc.subject | growth inhibition | |
dc.subject | human | |
dc.subject | human cell | |
dc.subject | mouse | |
dc.subject | Mycobacterium tuberculosis | |
dc.subject | nonhuman | |
dc.subject | plasma protein binding | |
dc.subject | priority journal | |
dc.subject | animal | |
dc.subject | antagonists and inhibitors | |
dc.subject | drug design | |
dc.subject | drug effects | |
dc.subject | genetics | |
dc.subject | lung tuberculosis | |
dc.subject | microbial sensitivity test | |
dc.subject | microbiology | |
dc.subject | molecular model | |
dc.subject | Mycobacterium smegmatis | |
dc.subject | Animals | |
dc.subject | Anti-Bacterial Agents | |
dc.subject | Bacterial Proteins | |
dc.subject | Bortezomib | |
dc.subject | Drug Design | |
dc.subject | Endopeptidase Clp | |
dc.subject | Mice | |
dc.subject | Microbial Sensitivity Tests | |
dc.subject | Models, Molecular | |
dc.subject | Mycobacterium smegmatis | |
dc.subject | Mycobacterium tuberculosis | |
dc.subject | Proteasome Inhibitors | |
dc.subject | Serine Endopeptidases | |
dc.subject | Tuberculosis, Pulmonary | |
dc.type | Article | |
dc.contributor.department | MICROBIOLOGY AND IMMUNOLOGY | |
dc.contributor.department | PHARMACY | |
dc.contributor.department | CHEMISTRY | |
dc.description.doi | 10.1128/AAC.02307-16 | |
dc.description.sourcetitle | Antimicrobial Agents and Chemotherapy | |
dc.description.volume | 61 | |
dc.description.issue | 5 | |
dc.description.page | e02307 | |
dc.published.state | Published | |
Appears in Collections: | Staff Publications Elements |
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