A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1

Abstract

Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously.

Combined Transcriptome and Proteome Profiling for Role of pfEMP1 in Antimalarial Mechanism of Action of Dihydroartemisinin

“…Targeting pfEMP1 or factors regulating var variants is expected to be applied as potential antimalarial therapy and as adjuvant therapy in ACTs. The observed changes in the transcriptome and the membrane proteome strongly support this notion, and recent studies have also suggested exploiting chromatin and/or epigenetic regulators as drug targets in malarial diseases ( 37 – 39 ), providing evidence for our hypothesis of targeting pfEMP1 or factors regulating var variants in new antimalarial drug development.…”

Ten-Year Molecular Surveillance of Drug-Resistant Plasmodium spp. Isolated From the China–Myanmar Border

“…These results indicated that the artemisinin resistance marker Pfk13 mutations are very complex and exhibited an increasing trend. Our study provides a strong theoretical basis for subsequent ACTs, but new mutant loci that are directly related to developing resistance by in vitro parasites require to be studied further using allelic exchange genetic modification methods, such as CRISPR/Cas9 genomic editing, combined with in vitro drug screening tests ( Xiao et al., 2019 ; Huang et al., 2020 ). The mechanism of action of artemisinin remains controversial, and our study provides some evidence of artemisinin drug resistance.…”

PfHDAC1 is an essential regulator of parasite asexual growth with its altered genomic occupancy and activity associated with artemisinin drug resistance in Plasmodium falciparum

“…Although PfHDAC1 has been described as a target of multiple highly potent inhibitors, a thorough genetic and biological characterization of PfHDAC1 function is lacking in P. falciparum [19, 34-36]. To characterize its enzymatic activity, we cloned, expressed, and purified histidine- and GST-tagged PfHDAC1 (Figure 1A and 1B).…”