Accelerating Antimalarial Drug Discovery with a New High-Throughput Screen for Fast-Killing Compounds.

Autor: Sakura T; Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan.; School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan., Ishii R; Department of Cellular Architecture Studies, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan.; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka 561-0825, Japan., Yoshida E; Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan., Kita K; School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan.; Department of Infection Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan.; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan., Kato T; Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., Osaka 561-0825, Japan.; Exploratory Research for Drug Discovery, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan., Inaoka DK; Department of Molecular Infection Dynamics, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan.; School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan.; Department of Infection Biochemistry, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki 852-8523, Japan.; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2024 Dec 13; Vol. 10 (12), pp. 4115-4126. Date of Electronic Publication: 2024 Nov 19.
DOI: 10.1021/acsinfecdis.4c00328
Abstrakt: The urgent need for rapidly acting compounds in the development of antimalarial drugs underscores the significance of such compounds in overcoming resistance issues and improving patient adherence to antimalarial treatments. The present study introduces a high-throughput screening (HTS) approach using 1536-well plates, employing Plasmodium falciparum lactate dehydrogenase (PfLDH) combined with nitroreductase (NTR) and fluorescent probes to evaluate inhibition of the growth of the asexual blood stage of malaria parasites. This method was adapted to efficiently assess the speed of action profiling (SAP) in a 384-well plate format, streamlining the traditionally time-consuming screening process. By successfully screening numerous compounds, this approach identified fast-killing hits early in the screening process, addressing challenges associated with artemisinin-based combination therapies. The high-throughput SAP method is expected to be of value in continuously monitoring fast-killing properties during structure-activity relationship studies, expediting the identification and development of novel, rapidly acting antimalarial drugs within phenotypic drug discovery campaigns.
Databáze: MEDLINE
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