The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs
The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an in...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2016
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| Online Access: | http://hdl.handle.net/1721.1/105581 https://orcid.org/0000-0003-2816-6195 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1826216587599806464 |
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| author | Pepper, L. R. Cortese, J. F. Estiu, G. Galinsky, K. Zuzarte-Luis, V. Derbyshire, E. R. Ribacke, U. Lukens, A. K. Santos, S. A. Patel, V. Clish, C. B. Sullivan, W. J. Zhou, H. Bopp, S. E. Schimmel, P. Clardy, J. Mota, M. M. Keller, T. L. Whitman, M. Wiest, O. Wirth, D. F. Mazitschek, R. Lindquist, Susan Herman, Jonathan D. |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Pepper, L. R. Cortese, J. F. Estiu, G. Galinsky, K. Zuzarte-Luis, V. Derbyshire, E. R. Ribacke, U. Lukens, A. K. Santos, S. A. Patel, V. Clish, C. B. Sullivan, W. J. Zhou, H. Bopp, S. E. Schimmel, P. Clardy, J. Mota, M. M. Keller, T. L. Whitman, M. Wiest, O. Wirth, D. F. Mazitschek, R. Lindquist, Susan Herman, Jonathan D. |
| author_sort | Pepper, L. R. |
| collection | MIT |
| description | The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl–tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials. |
| first_indexed | 2024-09-23T16:49:58Z |
| format | Article |
| id | mit-1721.1/105581 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:49:58Z |
| publishDate | 2016 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1055812022-09-29T21:50:28Z The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs Pepper, L. R. Cortese, J. F. Estiu, G. Galinsky, K. Zuzarte-Luis, V. Derbyshire, E. R. Ribacke, U. Lukens, A. K. Santos, S. A. Patel, V. Clish, C. B. Sullivan, W. J. Zhou, H. Bopp, S. E. Schimmel, P. Clardy, J. Mota, M. M. Keller, T. L. Whitman, M. Wiest, O. Wirth, D. F. Mazitschek, R. Lindquist, Susan Herman, Jonathan D. Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Biology Herman, Jonathan D Lindquist, Susan The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl–tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials. Howard Hughes Medical Institute 2016-12-05T19:17:05Z 2016-12-05T19:17:05Z 2015-05 Article http://purl.org/eprint/type/JournalArticle 1946-6234 1946-6242 http://hdl.handle.net/1721.1/105581 Herman, J. D. et al. “The Cytoplasmic Prolyl-tRNA Synthetase of the Malaria Parasite Is a Dual-Stage Target of Febrifugine and Its Analogs.” Science Translational Medicine 7.288 (2015): 288ra77-288ra77. https://orcid.org/0000-0003-2816-6195 https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1126/scitranslmed.aaa3575 Science Translational Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Pepper, L. R. Cortese, J. F. Estiu, G. Galinsky, K. Zuzarte-Luis, V. Derbyshire, E. R. Ribacke, U. Lukens, A. K. Santos, S. A. Patel, V. Clish, C. B. Sullivan, W. J. Zhou, H. Bopp, S. E. Schimmel, P. Clardy, J. Mota, M. M. Keller, T. L. Whitman, M. Wiest, O. Wirth, D. F. Mazitschek, R. Lindquist, Susan Herman, Jonathan D. The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs |
| title | The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs |
| title_full | The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs |
| title_fullStr | The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs |
| title_full_unstemmed | The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs |
| title_short | The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs |
| title_sort | cytoplasmic prolyl trna synthetase of the malaria parasite is a dual stage target of febrifugine and its analogs |
| url | http://hdl.handle.net/1721.1/105581 https://orcid.org/0000-0003-2816-6195 https://orcid.org/0000-0003-1307-882X |
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