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Mechanisms of Action: Physiological Effects

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

Utsav Sen, Akshaykumar Nayak, Juhi Khurana, Deepu Sharma, Ashish Gupta
Utsav Sen
aEpigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India
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Akshaykumar Nayak
aEpigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India
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Juhi Khurana
aEpigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India
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Deepu Sharma
aEpigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India
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Ashish Gupta
aEpigenetics and Human Disease Laboratory, Department of Life Sciences, Shiv Nadar University, Gautam Budh Nagar, Uttar Pradesh, India
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  • ORCID record for Ashish Gupta
DOI: 10.1128/AAC.00953-20
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ABSTRACT

One of the major barriers in the prevention and control of malaria programs worldwide is the growing emergence of multidrug resistance in Plasmodium 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 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, 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 P. falciparum 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.

FOOTNOTES

    • Received 11 May 2020.
    • Returned for modification 19 June 2020.
    • Accepted 1 October 2020.
    • Accepted manuscript posted online 12 October 2020.
  • Supplemental material is available online only.

  • Copyright © 2020 American Society for Microbiology.

All Rights Reserved.

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Inhibition of PfMYST Histone Acetyltransferase Activity Blocks Plasmodium falciparum Growth and Survival
Utsav Sen, Akshaykumar Nayak, Juhi Khurana, Deepu Sharma, Ashish Gupta
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e00953-20; DOI: 10.1128/AAC.00953-20

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Inhibition of PfMYST Histone Acetyltransferase Activity Blocks Plasmodium falciparum Growth and Survival
Utsav Sen, Akshaykumar Nayak, Juhi Khurana, Deepu Sharma, Ashish Gupta
Antimicrobial Agents and Chemotherapy Dec 2020, 65 (1) e00953-20; DOI: 10.1128/AAC.00953-20
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KEYWORDS

Plasmodium
PfMYST
NU9056
TIP60
HAT assay
Plasmodium falciparum
malaria

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