Abstract

Malaria is caused by infection with protozoan parasites of the Plasmodium genus, which is part of the phylum Apicomplexa. Most organisms in this phylum contain a relic plastid called the apicoplast. The apicoplast genome is replicated by a single DNA polymerase (apPOL), which is an attractive target for anti-malarial drugs. We screened small-molecule libraries (206,504 compounds) using a fluorescence-based high-throughput DNA polymerase assay. Dose/response analysis and counter-screening identified 186 specific apPOL inhibitors. Toxicity screening against human HepaRG human cells removed 84 compounds and the remaining were subjected to parasite killing assays using chloroquine resistant P. falciparum parasites. Nine compounds were potent inhibitors of parasite growth and may serve as lead compounds in efforts to discover novel malaria drugs.

Details

Title
Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase
Author
Kaur, Supreet 1 ; Nieto, Nicholas S 1 ; McDonald, Peter 2 ; Beck, Josh R 3 ; Honzatko, Richard B 1 ; Roy, Anuradha 2 ; Nelson, Scott W 1 

 Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA, USA 
 High Throughput Screening Laboratory, University of Kansas, Lawrence, KS, USA 
 Department of Biomedical Sciences, Iowa State University, Ames, IA, USA 
Pages
1320-1326
Publication year
2022
Publication date
Dec 2022
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2727915933
Copyright
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.