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Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts

Author

Listed:
  • Diego Rodríguez-Hernández

    (University of Gothenburg; S-405 30
    University of Bergen)

  • Kamalakannan Vijayan

    (Seattle Children’s Research Institute
    Indian Institute of Science Education and Research)

  • Rachael Zigweid

    (Seattle Children’s Research Institute
    Seattle Structural Genomics Center for Infectious Disease)

  • Michael K. Fenwick

    (Seattle Children’s Research Institute
    Seattle Structural Genomics Center for Infectious Disease)

  • Banumathi Sankaran

    (Advanced Light Source; Berkeley National Laboratory)

  • Wanlapa Roobsoong

    (Mahidol University)

  • Jetsumon Sattabongkot

    (Mahidol University)

  • Elizabeth K. K. Glennon

    (Seattle Children’s Research Institute)

  • Peter J. Myler

    (Seattle Children’s Research Institute
    Seattle Structural Genomics Center for Infectious Disease
    Department of Pediatrics, University of Washington)

  • Per Sunnerhagen

    (University of Gothenburg; S-405 30)

  • Bart L. Staker

    (Seattle Children’s Research Institute
    Seattle Structural Genomics Center for Infectious Disease)

  • Alexis Kaushansky

    (Seattle Children’s Research Institute
    Department of Pediatrics, University of Washington)

  • Morten Grøtli

    (University of Gothenburg; S-405 30)

Abstract

Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage.

Suggested Citation

  • Diego Rodríguez-Hernández & Kamalakannan Vijayan & Rachael Zigweid & Michael K. Fenwick & Banumathi Sankaran & Wanlapa Roobsoong & Jetsumon Sattabongkot & Elizabeth K. K. Glennon & Peter J. Myler & Pe, 2023. "Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41119-7
    DOI: 10.1038/s41467-023-41119-7
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    References listed on IDEAS

    as
    1. Cyril Dian & Inmaculada Pérez-Dorado & Frédéric Rivière & Thomas Asensio & Pierre Legrand & Markus Ritzefeld & Mengjie Shen & Ernesto Cota & Thierry Meinnel & Edward W. Tate & Carmela Giglione, 2020. "High-resolution snapshots of human N-myristoyltransferase in action illuminate a mechanism promoting N-terminal Lys and Gly myristoylation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    2. Alison Roth & Steven P. Maher & Amy J. Conway & Ratawan Ubalee & Victor Chaumeau & Chiara Andolina & Stephen A. Kaba & Amélie Vantaux & Malina A. Bakowski & Richard Thomson-Luque & Swamy Rakesh Adapa , 2018. "Author Correction: A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
    3. Alison Roth & Steven P. Maher & Amy J. Conway & Ratawan Ubalee & Victor Chaumeau & Chiara Andolina & Stephen A. Kaba & Amélie Vantaux & Malina A. Bakowski & Richard Thomson-Luque & Swamy Rakesh Adapa , 2018. "A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    4. Tatsiana Kosciuk & Ian R. Price & Xiaoyu Zhang & Chengliang Zhu & Kayla N. Johnson & Shuai Zhang & Steve L. Halaby & Garrison P. Komaniecki & Min Yang & Caroline J. DeHart & Paul M. Thomas & Neil L. K, 2020. "NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
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