Inhibition of PfMYST Histone Acetyltransferase Activity Blocks Plasmodium falciparum Growth and Survival

Abstract

One of the major barrier in the prevention & control of malaria programs worldwide is the growing emergence of multidrug-resistance in Plasmodium parasite and demands continued efforts to discover & develop effective drug molecules targeting novel proteins essential for parasite survival. In recent years, epigenetic regulators have evolved as an attractive drug target option owing to their crucial role in survival and development of Plasmodium at different stages of its life cycle. PfMYST, a histone acetyltransferase protein, is known to regulate key cellular processes such as cell-cycle progression, DNA damage repair & antigenic variation that facilitates parasite growth, adaptation & survival inside its host. With an aim to assess the therapeutic potential of PfMYST as a novel drug target, we have examined the effect of NU9056 (a HsTIP60 inhibitor) on the rate of parasite growth and survival. In the present study, by using yeast complementation assay we have established that PfMYST is a true homolog of TIP60 protein and have shown that NU9056 can inhibit PfMYST catalytic activity and kill P. falciparum parasite in culture. Inhibiting the catalytic activity of PfMYST, arrests the parasite in trophozoite stage and inhibits its further transition to schizont stage, eventually leading to its death. Overall, our study provides proof of concept that PfMYST catalytic activity is essential for parasite growth & survival and PfMYST can be a potential target for anti-malarial therapy.

Integration of population and functional genomics to understand mechanisms of artemisinin resistance in Plasmodium falciparum

“…PfMYST was also demonstrated to participate in var gene activation, as well as DNA repair, and to modulate sensitivity to genotoxic agents. HAT inhibitors have been shown in previous studies to have parasiticidal effects ( Andrews et al, 2000 ; Cui et al, 2007 ; Darkin-Rattray et al, 1996 ; Sen et al, 2020 ), lending credence to the possibility of histone acetylation enzymes as antimalarial drug targets.…”

Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum

“…This compound with an IC 50 at 200 nM range in parasite growth assay is tenfold less active against human cancer cells and shows no effect against mammalian fibroblast cells up to 20 µM [ 117 ]. Pf MYST is potentially another interesting target as it also differs significantly from its human orthologue and NU9056, a thiazole derivative, inhibiting Pf MYST catalytic activity is lethal for the parasite at a micromolar range [ 118 ] (Table 2 ). Although few Plasmodium HAT inhibitors have been described to date, new compounds designed to target HATs, involved in different pathologies, remain to be evaluated on the parasite and may provide interesting chemical starting points [ 119 ].…”

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

“…PfMYST presents another target due to its dissimilarity to its human counterpart. The thiazole derivative NU9056, known for inhibiting PfMYST catalytic activity, proves lethal for the parasite at a micromolar range [ 330 ]. Despite the limited number of described Plasmodium HAT inhibitors thus far, there is a need to assess new compounds designed to target HATs.…”