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Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors

Author

Listed:
  • Hao-Chi Hsu

    (Van Andel Institute)

  • Daqiang Li

    (Weill Cornell Medicine)

  • Wenhu Zhan

    (Weill Cornell Medicine)

  • Jianxiang Ye

    (Weill Cornell Medicine)

  • Yi Jing Liu

    (Weill Cornell Medicine)

  • Annie Leung

    (Weill Cornell Medicine)

  • Junling Qin

    (University of South Florida)

  • Benigno Crespo

    (GlaxoSmithKline)

  • Francisco-Javier Gamo

    (GlaxoSmithKline)

  • Hao Zhang

    (Weill Cornell Medicine)

  • Liwang Cui

    (University of South Florida
    University of South Florida)

  • Alison Roth

    (Experimental Therapeutics Branch, The Walter Reed Army Institute of Research)

  • Laura A. Kirkman

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Huilin Li

    (Van Andel Institute)

  • Gang Lin

    (Weill Cornell Medicine)

Abstract

The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6A117D with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6A117D. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.

Suggested Citation

  • Hao-Chi Hsu & Daqiang Li & Wenhu Zhan & Jianxiang Ye & Yi Jing Liu & Annie Leung & Junling Qin & Benigno Crespo & Francisco-Javier Gamo & Hao Zhang & Liwang Cui & Alison Roth & Laura A. Kirkman & Huil, 2023. "Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44077-2
    DOI: 10.1038/s41467-023-44077-2
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    References listed on IDEAS

    as
    1. 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.
    2. Shilpi Khare & Advait S. Nagle & Agnes Biggart & Yin H. Lai & Fang Liang & Lauren C. Davis & S. Whitney Barnes & Casey J. N. Mathison & Elmarie Myburgh & Mu-Yun Gao & J. Robert Gillespie & Xianzhong L, 2016. "Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness," Nature, Nature, vol. 537(7619), pages 229-233, September.
    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. Hao Li & Anthony J. O’Donoghue & Wouter A. van der Linden & Stanley C. Xie & Euna Yoo & Ian T. Foe & Leann Tilley & Charles S. Craik & Paula C. A. da Fonseca & Matthew Bogyo, 2016. "Structure- and function-based design of Plasmodium-selective proteasome inhibitors," Nature, Nature, vol. 530(7589), pages 233-236, February.
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