IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-44077-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-44077-2
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-44077-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jan Silhan & Pavla Fajtova & Jitka Bartosova & Brianna M. Hurysz & Jehad Almaliti & Yukiko Miyamoto & Lars Eckmann & William H. Gerwick & Anthony J. O’Donoghue & Evzen Boura, 2024. "Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. 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.
    3. Annie S. P. Yang & Devanjali Dutta & Kai Kretzschmar & Delilah Hendriks & Jens Puschhof & Huili Hu & Kim E. Boonekamp & Youri Waardenburg & Susana M. Chuva de Sousa Lopes & Geert-Jan Gemert & Johannes, 2023. "Development of Plasmodium falciparum liver-stages in hepatocytes derived from human fetal liver organoid cultures," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Archie A. Khan & Harry C. Langston & Louis Walsh & Rebecca Roscoe & Shiromani Jayawardhana & Amanda Fortes Francisco & Martin C. Taylor & Conor J. McCann & John M. Kelly & Michael D. Lewis, 2024. "Enteric nervous system regeneration and functional cure of experimental digestive Chagas disease with trypanocidal chemotherapy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Catarina A. Marques & Melanie Ridgway & Michele Tinti & Andrew Cassidy & David Horn, 2022. "Genome-scale RNA interference profiling of Trypanosoma brucei cell cycle progression defects," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Ruixue Xu & Lirong Lin & Zhiwei Jiao & Rui Liang & Yazhen Guo & Yixin Zhang & Xiaoxu Shang & Yuezhou Wang & Xu Wang & Luming Yao & Shengfa Liu & Xianming Deng & Jing Yuan & Xin-zhuan Su & Jian Li, 2024. "Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Jaishree Tripathi & Lei Zhu & Sourav Nayak & Michal Stoklasa & Zbynek Bozdech, 2022. "Stochastic expression of invasion genes in Plasmodium falciparum schizonts," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44077-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.