Discovery of small molecule inhibitors of Plasmodium falciparum apicoplast DNA polymerase

Journal of Enzyme Inhibition and Medicinal Chemistry

Scott W. Nelson¹  Nicholas S. Nieto¹  Richard B. Honzatko¹  Supreet Kaur¹  Josh R. Beck²  Peter McDonald³  Anuradha Roy³ 

[1] Department of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA, USA;Department of Biomedical Sciences, Iowa State University, Ames, IA, USA;High Throughput Screening Laboratory, University of Kansas, Lawrence, KS, USA;

关键词: Malaria;    high-throughput screening;    DNA polymerase;    apicoplast;   

DOI  :  10.1080/14756366.2022.2070909

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown