Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery
Plasmodium species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by Plasmodium parasites in the population co-infected with both HIV-1 and malaria. Ho...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Current Research in Structural Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2665928X24000059 |
| _version_ | 1797349468685729792 |
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| author | Vandana Mishra Anuradha Deshmukh Ishan Rathore Satadru Chakraborty Swati Patankar Alla Gustchina Alexander Wlodawer Rickey Y. Yada Prasenjit Bhaumik |
| author_facet | Vandana Mishra Anuradha Deshmukh Ishan Rathore Satadru Chakraborty Swati Patankar Alla Gustchina Alexander Wlodawer Rickey Y. Yada Prasenjit Bhaumik |
| author_sort | Vandana Mishra |
| collection | DOAJ |
| description | Plasmodium species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by Plasmodium parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating Plasmodium pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of P. falciparum. Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII via multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of P. falciparum PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs. |
| first_indexed | 2024-03-08T12:30:40Z |
| format | Article |
| id | doaj.art-e7224c26185441e3a44d611f95d5de71 |
| institution | Directory Open Access Journal |
| issn | 2665-928X |
| language | English |
| last_indexed | 2024-03-08T12:30:40Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Structural Biology |
| spelling | doaj.art-e7224c26185441e3a44d611f95d5de712024-01-22T04:16:11ZengElsevierCurrent Research in Structural Biology2665-928X2024-01-017100128Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discoveryVandana Mishra0Anuradha Deshmukh1Ishan Rathore2Satadru Chakraborty3Swati Patankar4Alla Gustchina5Alexander Wlodawer6Rickey Y. Yada7Prasenjit Bhaumik8Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, IndiaDepartment of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, IndiaDepartment of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India; Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, 21702, USADepartment of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, IndiaDepartment of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, IndiaProtein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, 21702, USAProtein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, 21702, USAFaculty of Land and Food Systems, University of British Columbia, 248-2357 Main Mall, Vancouver, BC V6T 1Z4, Vancouver, CanadaDepartment of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, India; Corresponding author.Plasmodium species are causative agents of malaria, a disease that is a serious global health concern. FDA-approved HIV-1 protease inhibitors (HIV-1 PIs) have been reported to be effective in reducing the infection by Plasmodium parasites in the population co-infected with both HIV-1 and malaria. However, the mechanism of HIV-1 PIs in mitigating Plasmodium pathogenesis during malaria/HIV-1 co-infection is not fully understood. In this study we demonstrate that HIV-1 drugs ritonavir (RTV) and lopinavir (LPV) exhibit the highest inhibition activity against plasmepsin II (PMII) and plasmepsin X (PMX) of P. falciparum. Crystal structures of the complexes of PMII with both drugs have been determined. The inhibitors interact with PMII via multiple hydrogen bonding and hydrophobic interactions. The P4 moiety of RTV forms additional interactions compared to LPV and exhibits conformational flexibility in a large S4 pocket of PMII. Our study is also the first to report inhibition of P. falciparum PMX by RTV and the mode of binding of the drug to the PMX active site. Analysis of the crystal structures implies that PMs can accommodate bulkier groups of these inhibitors in their S4 binding pockets. Structurally similar active sites of different vacuolar and non-vacuolar PMs suggest the potential of HIV-1 PIs in targeting these enzymes with differential affinities. Our structural investigations and biochemical data emphasize PMs as crucial targets for repurposing HIV-1 PIs as antimalarial drugs.http://www.sciencedirect.com/science/article/pii/S2665928X24000059PlasmepsinsProteaseParasiteMalariaHemoglobinDrug design |
| spellingShingle | Vandana Mishra Anuradha Deshmukh Ishan Rathore Satadru Chakraborty Swati Patankar Alla Gustchina Alexander Wlodawer Rickey Y. Yada Prasenjit Bhaumik Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery Current Research in Structural Biology Plasmepsins Protease Parasite Malaria Hemoglobin Drug design |
| title | Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery |
| title_full | Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery |
| title_fullStr | Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery |
| title_full_unstemmed | Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery |
| title_short | Inhibition of Plasmodium falciparum plasmepsins by drugs targeting HIV-1 protease: A way forward for antimalarial drug discovery |
| title_sort | inhibition of plasmodium falciparum plasmepsins by drugs targeting hiv 1 protease a way forward for antimalarial drug discovery |
| topic | Plasmepsins Protease Parasite Malaria Hemoglobin Drug design |
| url | http://www.sciencedirect.com/science/article/pii/S2665928X24000059 |
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