Journal article
Promising antimalarials targeting apicoplast DNA polymerase from Plasmodium falciparum
European journal of medicinal chemistry, Vol.243, pp.114751-114751
12/05/2022
DOI: 10.1016/j.ejmech.2022.114751
PMID: 36191407
Abstract
Malaria is caused by the parasite Plasmodium falciparum, which contains an essential non-photosynthetic plastid called the apicoplast. A single DNA polymerase, apPOL, is targeted to the apicoplast, where it replicates and repairs the genome. apPOL has no direct orthologs in mammals and is considered a promising drug target for the treatment and/or prevention of malaria. We previously reported screening the Malaria Box to identify MMV666123 as an inhibitor of apPOL. Herein we extend our studies and report structure-activity relationships for MMV666123 and identify key structural motifs necessary for inhibition. Although attempts to crystallize apPOL with the inhibitor were not fruitful, kinetic analysis and crystal structure determinations of WT and mutant apo-enzymes, facilitated model building and provided insights into the putative inhibitor binding site. Our results validate apPOL as an antimalarial target and provide an avenue for the design of high potency, specific inhibitors of apPOL and other A-family DNA polymerases.
Details
- Title: Subtitle
- Promising antimalarials targeting apicoplast DNA polymerase from Plasmodium falciparum
- Creators
- Pratik R. Chheda - University of IowaNicholas Nieto - Iowa State UniversitySupreet Kaur - Iowa State UniversityJohn M. Beck - Iowa State UniversityJosh R. Beck - Iowa State UniversityRichard Honzatko - Iowa State UniversityRobert J. Kerns - Univ Iowa, Coll Pharm, Dept Pharmaceut Sci & Expt Therapeut, Div Med & Nat Prod Chem, 115 S Grand Ave,S321 Pharm Bldg, Iowa City, IA 52242 USAScott W. Nelson - Iowa State University
- Resource Type
- Journal article
- Publication Details
- European journal of medicinal chemistry, Vol.243, pp.114751-114751
- Publisher
- Elsevier
- DOI
- 10.1016/j.ejmech.2022.114751
- PMID
- 36191407
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Number of pages
- 16
- Grant note
- University of Iowa Center for Biocatalysis and Bioprocessing R21AI127622 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32 GM008365 / NIH sponsored Predoctoral Training Program in Biotechnology; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA University of Iowa College of Pharmacy research stimulation funds John L. and Carol E. Lach Chair in Drug Delivery Technology
- Language
- English
- Date published
- 12/05/2022
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984366021002771
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