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Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance

Author

Listed:
  • Mark A. Tye

    (Massachusetts General Hospital
    Harvard Graduate School of Arts and Sciences
    Harvard T.H. Chan School of Public Health)

  • N. Connor Payne

    (Massachusetts General Hospital
    Harvard University)

  • Catrine Johansson

    (University of Oxford
    University of Oxford)

  • Kritika Singh

    (Massachusetts General Hospital
    Northeastern University)

  • Sofia A. Santos

    (Massachusetts General Hospital)

  • Lọla Fagbami

    (Massachusetts General Hospital
    Harvard Graduate School of Arts and Sciences
    Harvard T.H. Chan School of Public Health
    Broad Institute of MIT and Harvard)

  • Akansha Pant

    (Harvard T.H. Chan School of Public Health)

  • Kayla Sylvester

    (Duke University)

  • Madeline R. Luth

    (University of California, San Diego)

  • Sofia Marques

    (Universidade de Lisboa)

  • Malcolm Whitman

    (Harvard School of Dental Medicine)

  • Maria M. Mota

    (Universidade de Lisboa)

  • Elizabeth A. Winzeler

    (University of California, San Diego)

  • Amanda K. Lukens

    (Broad Institute of MIT and Harvard)

  • Emily R. Derbyshire

    (Duke University)

  • Udo Oppermann

    (University of Oxford
    University of Oxford)

  • Dyann F. Wirth

    (Harvard T.H. Chan School of Public Health
    Broad Institute of MIT and Harvard)

  • Ralph Mazitschek

    (Massachusetts General Hospital
    Harvard T.H. Chan School of Public Health
    Broad Institute of MIT and Harvard)

Abstract

The development of next-generation antimalarials that are efficacious against the human liver and asexual blood stages is recognized as one of the world’s most pressing public health challenges. In recent years, aminoacyl-tRNA synthetases, including prolyl-tRNA synthetase, have emerged as attractive targets for malaria chemotherapy. We describe the development of a single-step biochemical assay for Plasmodium and human prolyl-tRNA synthetases that overcomes critical limitations of existing technologies and enables quantitative inhibitor profiling with high sensitivity and flexibility. Supported by this assay platform and co-crystal structures of representative inhibitor-target complexes, we develop a set of high-affinity prolyl-tRNA synthetase inhibitors, including previously elusive aminoacyl-tRNA synthetase triple-site ligands that simultaneously engage all three substrate-binding pockets. Several compounds exhibit potent dual-stage activity against Plasmodium parasites and display good cellular host selectivity. Our data inform the inhibitor requirements to overcome existing resistance mechanisms and establish a path for rational development of prolyl-tRNA synthetase-targeted anti-malarial therapies.

Suggested Citation

  • Mark A. Tye & N. Connor Payne & Catrine Johansson & Kritika Singh & Sofia A. Santos & Lọla Fagbami & Akansha Pant & Kayla Sylvester & Madeline R. Luth & Sofia Marques & Malcolm Whitman & Maria M. Mota, 2022. "Elucidating the path to Plasmodium prolyl-tRNA synthetase inhibitors that overcome halofuginone resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32630-4
    DOI: 10.1038/s41467-022-32630-4
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    References listed on IDEAS

    as
    1. Pengfei Fang & Xue Yu & Seung Jae Jeong & Adam Mirando & Kaige Chen & Xin Chen & Sunghoon Kim & Christopher S. Francklyn & Min Guo, 2015. "Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    2. Huihao Zhou & Litao Sun & Xiang-Lei Yang & Paul Schimmel, 2013. "ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase," Nature, Nature, vol. 494(7435), pages 121-124, February.
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