Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts
Abstract Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhi...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41119-7 |
| _version_ | 1797557907397541888 |
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| author | Diego Rodríguez-Hernández Kamalakannan Vijayan Rachael Zigweid Michael K. Fenwick Banumathi Sankaran Wanlapa Roobsoong Jetsumon Sattabongkot Elizabeth K. K. Glennon Peter J. Myler Per Sunnerhagen Bart L. Staker Alexis Kaushansky Morten Grøtli |
| author_facet | Diego Rodríguez-Hernández Kamalakannan Vijayan Rachael Zigweid Michael K. Fenwick Banumathi Sankaran Wanlapa Roobsoong Jetsumon Sattabongkot Elizabeth K. K. Glennon Peter J. Myler Per Sunnerhagen Bart L. Staker Alexis Kaushansky Morten Grøtli |
| author_sort | Diego Rodríguez-Hernández |
| collection | DOAJ |
| description | Abstract Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage. |
| first_indexed | 2024-03-10T17:22:55Z |
| format | Article |
| id | doaj.art-e6b4e2ed37a24eb3abab00e4f5cd5476 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:22:55Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-e6b4e2ed37a24eb3abab00e4f5cd54762023-11-20T10:17:25ZengNature PortfolioNature Communications2041-17232023-09-0114111310.1038/s41467-023-41119-7Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizontsDiego Rodríguez-Hernández0Kamalakannan Vijayan1Rachael Zigweid2Michael K. Fenwick3Banumathi Sankaran4Wanlapa Roobsoong5Jetsumon Sattabongkot6Elizabeth K. K. Glennon7Peter J. Myler8Per Sunnerhagen9Bart L. Staker10Alexis Kaushansky11Morten Grøtli12Department of Chemistry and Molecular Biology, University of Gothenburg; S-405 30Center for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteMolecular Biophysics and Integrated Bioimaging, Berkeley Center for Structural Biology, Advanced Light Source; Berkeley National LaboratoryMahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol UniversityMahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol UniversityCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteDepartment of Chemistry and Molecular Biology, University of Gothenburg; S-405 30Center for Global Infectious Disease Research, Seattle Children’s Research InstituteCenter for Global Infectious Disease Research, Seattle Children’s Research InstituteDepartment of Chemistry and Molecular Biology, University of Gothenburg; S-405 30Abstract Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage.https://doi.org/10.1038/s41467-023-41119-7 |
| spellingShingle | Diego Rodríguez-Hernández Kamalakannan Vijayan Rachael Zigweid Michael K. Fenwick Banumathi Sankaran Wanlapa Roobsoong Jetsumon Sattabongkot Elizabeth K. K. Glennon Peter J. Myler Per Sunnerhagen Bart L. Staker Alexis Kaushansky Morten Grøtli Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts Nature Communications |
| title | Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts |
| title_full | Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts |
| title_fullStr | Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts |
| title_full_unstemmed | Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts |
| title_short | Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts |
| title_sort | identification of potent and selective n myristoyltransferase inhibitors of plasmodium vivax liver stage hypnozoites and schizonts |
| url | https://doi.org/10.1038/s41467-023-41119-7 |
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