Epigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India.
Epigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India
Antimicrob Agents Chemother. 2020 Dec 16;65(1). doi: 10.1128/AAC.00953-20.
One of the major barriers in the prevention and control of malaria programs worldwide is the growing emergence of multidrug resistance in parasites, and this necessitates continued efforts to discover and 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 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, and antigenic variation, that facilitate parasite growth, adaptation, and survival inside its host. With the aim of assessing the therapeutic potential of PfMYST as a novel drug target, we examined the effect of NU9056 (an HsTIP60 inhibitor) on the rate of parasite growth and survival. In the present study, by using a yeast complementation assay, we established that PfMYST is a true homolog of TIP60 and showed that NU9056 can inhibit PfMYST catalytic activity and kill parasites in culture. Inhibiting the catalytic activity of PfMYST arrests the parasite in the trophozoite stage and inhibits its further transition to the schizont stage, eventually leading to its death. Overall, our study provides proof of concept that PfMYST catalytic activity is essential for parasite growth and survival and that PfMYST can be a potential target for antimalarial therapy.
在全球疟疾防控计划中，一个主要障碍是寄生虫的多药耐药性日益显现，这需要持续努力发现和开发针对寄生虫生存所必需的新型蛋白质的有效药物分子。近年来，表观遗传调节剂因其在寄生虫生命周期不同阶段的生存和发育中的关键作用，已成为有吸引力的药物靶点选择。PfMYST 是一种组蛋白乙酰转移酶蛋白，已知可调节关键细胞过程，如细胞周期进程、DNA 损伤修复和抗原变异，这些过程有利于寄生虫在其宿主内的生长、适应和生存。为了评估 PfMYST 作为新型药物靶点的治疗潜力，我们研究了 NU9056（一种 HsTIP60 抑制剂）对寄生虫生长和存活速度的影响。在本研究中，我们通过酵母互补测定法确定 PfMYST 是 TIP60 的真正同源物，并表明 NU9056 可以抑制 PfMYST 的催化活性并杀死培养中的寄生虫。抑制 PfMYST 的催化活性会使寄生虫停滞在滋养体阶段，并阻止其进一步转化为裂殖体阶段，最终导致其死亡。总的来说，我们的研究提供了概念验证，证明 PfMYST 的催化活性对寄生虫的生长和存活至关重要，并且 PfMYST 可能是抗疟治疗的潜在靶点。
