Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry

Autor:	Gregory M. Cook, Jianying Han, Miaomiao Liu, Garry W. Buchko, Ronald J. Quinn, Yunjiang Feng, Joseph A. Laureanti, Tin Mak, Ali R. Elnaas, Darren Grice, Peter J. Myler, Angela Di Capua
Rok vydání:	2020
Předmět:	Tuberculosis native mass spectrometry Pharmaceutical Science Rv1466 01 natural sciences drug target Analytical Chemistry lcsh:QD241-441 Mycobacterium tuberculosis 03 medical and health sciences Minimum inhibitory concentration chemistry.chemical_compound lcsh:Organic chemistry Drug Discovery medicine Physical and Theoretical Chemistry 030304 developmental biology 0303 health sciences Natural product biology 010405 organic chemistry Drug discovery Chemistry Organic Chemistry biology.organism_classification medicine.disease 0104 chemical sciences tuberculosis Mechanism of action Drug development Biochemistry Chemistry (miscellaneous) Proteome Molecular Medicine medicine.symptom altholactone
Zdroj:	Molecules Volume 25 Issue 10 Molecules, Vol 25, Iss 2384, p 2384 (2020)
ISSN:	1420-3049
DOI:	10.3390/molecules25102384
Popis:	Elucidation of the mechanism of action of compounds with cellular bioactivity is important for progressing compounds into future drug development. In recent years, phenotype-based drug discovery has become the dominant approach to drug discovery over target-based drug discovery, which relies on the knowledge of a specific drug target of a disease. Still, when targeting an infectious disease via a high throughput phenotypic assay it is highly advantageous to identifying the compound&rsquo s cellular activity. A fraction derived from the plant Polyalthia sp. showed activity against Mycobacterium tuberculosis at 62.5 &mu ge/&mu L. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 &mu M. Retrospective analysis of a target-based screen against a TB proteome panel using native mass spectrometry established that the active fraction was bound to the mycobacterial protein Rv1466 with an estimated pseudo-Kd of 42.0 ± 6.1 µ M. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards M. tuberculosis.
Databáze:	OpenAIRE
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