RT Journal Article
SR Electronic
T1 Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against <em>Plasmodium falciparum</em>
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.19.517177
DO 10.1101/2022.11.19.517177
A1 Tanyaluck Kampoun
A1 Pimpisid Koonyosying
A1 Jetsada Ruangsuriya
A1 Parichat Prommana
A1 Philip J. Shaw
A1 Sumalee Kamchonwongpaisan
A1 Hery Suwito
A1 Ni Nyoman Tri Puspaningsih
A1 Chairat Uthaipibull
A1 Somdet Srichairatanakool
YR 2022
UL http://biorxiv.org/content/early/2022/11/20/2022.11.19.517177.abstract
AB The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria and mutations in the propeller domains of P. falciparum Kelch13 (k13) are strongly associated with the resistance. Ferredoxin (Fd) in the ferredoxin/NADP+ reductase (Fd/FNR) redox system is essential for isoprenoid precursor synthesis in the plasmodial apicoplast; nonetheless, mutations of Fd gene (fd) may modulate ART resistance and Fd would be an important target for antimalarial drugs. We investigated the inhibitory effects of dihydroartemisinin (DHA), methoxyamino chalcone (C3), and iron chelators including deferiprone (DFP), 1-(N-acety1-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against the growth of wild-type (WT) P. falciparum parasites and those with k13 and fd mutations. C3 showed antimalarial potency similar to the iron chelators. Surprisingly, combined treatments of DHA with the C3 or iron chelators showed moderately antagonistic effects against P. falciparum growth. No differences were observed among the mutant parasites with respect to their sensitivity to C3 and the chelators, or the interactions of these compounds with DHA. The data suggest that inhibitors of the Fd/FNR redox system should be avoided as ART partner drugs in ART combination therapy for treating malaria.Competing Interest StatementThe authors have declared no competing interest.ANOVAanalysis of variancearps10apicoplast ribosomal protein S10 geneARTartemisininCIconfidential intervalCM11-(A-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-onecrtchloroquine-resistant transporter geneC3Fd-FNR inhibitor compound 3DFOdesferrioxiamineDFPdeferiproneDFP-RVTdeferiprone-resveratrol hybridDFXdeferasorixDHAdihydroartemisininDIdeionized waterDMSOdimethyl sulfoxideFdferredoxinfdferredoxin genefd-D193Yfd mutationFe-Siron-sulfurFIfluorescence intensityFICfractional inhibition concentrationFICfractional inhibition concentration indexFNRferredoxin NADP+ reductaseHEPEShydroxyethylpiperazine ethanosulfonic acidIC50inhibitory concentration 50%K13Kelch 13k13Kelch 13 genek13C580Y mutant and k13MTfdMT mutantk13 gene mutantmdr2multidrug resistance protein 2P. falciparumPlasmodium falciparumMSFmalaria SYBR Green I-based fluorescenceROSreactive oxygen species.