Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors
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 selecti...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44077-2 |
| _version_ | 1797388228578246656 |
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| author | 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 Huilin Li Gang Lin |
| author_facet | 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 Huilin Li Gang Lin |
| author_sort | Hao-Chi Hsu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T22:37:46Z |
| format | Article |
| id | doaj.art-c572579ac9434308b55f8122c4687613 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T22:37:46Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-c572579ac9434308b55f8122c46876132023-12-17T12:21:56ZengNature PortfolioNature Communications2041-17232023-12-0114111210.1038/s41467-023-44077-2Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitorsHao-Chi Hsu0Daqiang Li1Wenhu Zhan2Jianxiang Ye3Yi Jing Liu4Annie Leung5Junling Qin6Benigno Crespo7Francisco-Javier Gamo8Hao Zhang9Liwang Cui10Alison Roth11Laura A. Kirkman12Huilin Li13Gang Lin14Department of Structural Biology, Van Andel InstituteDepartment of Microbiology & Immunology, Weill Cornell MedicineDepartment of Microbiology & Immunology, Weill Cornell MedicineDepartment of Microbiology & Immunology, Weill Cornell MedicineDivision of Infectious Diseases, Department of Medicine, Weill Cornell MedicineDivision of Infectious Diseases, Department of Medicine, Weill Cornell MedicineDepartment of Internal Medicine, Morsani College of Medicine, University of South FloridaGlobal Health Medicines R&D, GlaxoSmithKlineGlobal Health Medicines R&D, GlaxoSmithKlineDepartment of Microbiology & Immunology, Weill Cornell MedicineDepartment of Internal Medicine, Morsani College of Medicine, University of South FloridaDepartment of Drug Discovery, Experimental Therapeutics Branch, The Walter Reed Army Institute of ResearchDepartment of Microbiology & Immunology, Weill Cornell MedicineDepartment of Structural Biology, Van Andel InstituteDepartment of Microbiology & Immunology, Weill Cornell MedicineAbstract 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.https://doi.org/10.1038/s41467-023-44077-2 |
| spellingShingle | 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 Huilin Li Gang Lin Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors Nature Communications |
| title | Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors |
| title_full | Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors |
| title_fullStr | Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors |
| title_full_unstemmed | Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors |
| title_short | Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors |
| title_sort | structures revealing mechanisms of resistance and collateral sensitivity of plasmodium falciparum to proteasome inhibitors |
| url | https://doi.org/10.1038/s41467-023-44077-2 |
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