Discovery of novel Leishmania major trypanothione synthetase inhibitors by high-throughput screening.

Autor: Phan TN; Host-Parasite Research Laboratory, Discovery Biology, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea., Park KP; Screening Discovery Platform, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea., Benítez D; Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay., Comini MA; Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay., Shum D; Screening Discovery Platform, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea., No JH; Host-Parasite Research Laboratory, Discovery Biology, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea. Electronic address: joohwan.no@ip-korea.org.
Jazyk: angličtina
Zdroj: Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2022 Dec 31; Vol. 637, pp. 308-313. Date of Electronic Publication: 2022 Nov 17.
DOI: 10.1016/j.bbrc.2022.11.044
Abstrakt: Leishmaniasis is an infectious disease caused by obligate intracellular protozoa of the genus Leishmania with high infection and death rates in developing countries. New drugs with better pharmacological performance with regards to safety, efficacy, toxicity, and drug resistance than those/the ones currently used are urgently needed. Trypanothione synthetase (TryS) is an attractive target for the development of drugs against leishmaniasis because it is specific and essential to kinetoplastid parasites. In this study, Leishmaniamajor TryS was expressed and purified, and the kinetic parameters of purified TryS were determined. To identify novel inhibitors of LmTryS, a high-throughput screening (HTS) assay was developed and used to screen a library of 35,040 compounds. In the confirmatory assay, 42 compounds displayed half maximal inhibitory concentration (IC 50 ) values < 50 μM and six of them corresponded to novel structures with IC 50 ranging from 9 to 19 μM against LmTryS enzyme activity. Of the six inhibitors, TS001 showed the highest activity against growth of L. major promastigotes, L. donovani promastigotes, and Trypanosoma brucei brucei Lister 427 with IC 50 values of 17, 26, and 31 μM, respectively. An in silico docking study using a homology model of LmTryS predicted the molecular interactions between LmTryS and the inhibitors.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
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