Towards Selective Mycobacterial ClpP1P2 Inhibitors with Reduced Activity against the Human Proteasome
| Autor: | Wilfried Moreira, Sridhar Santhanakrishnan, Anders Poulsen, Thomas Dick, Brian W. Dymock, Grace J. Y. Ngan, Kanda Sangthongpitag, Choon Bing Low |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Proteases medicine.medical_treatment Mycobacterium smegmatis Microbial Sensitivity Tests Pharmacology Mycobacterium tuberculosis Bortezomib 03 medical and health sciences chemistry.chemical_compound Mice Bacterial Proteins medicine Potency Animals Pharmacology (medical) Experimental Therapeutics dipeptidyl boronic acid Tuberculosis Pulmonary antimycobacterial Protease biology Serine Endopeptidases Endopeptidase Clp biology.organism_classification Anti-Bacterial Agents 030104 developmental biology Infectious Diseases chemistry Proteasome Drug Design Toxicity caseinolytic protease Lead compound Proteasome Inhibitors medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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