Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion
Proteases of the malaria parasite Plasmodium falciparum have long been investigated as drug targets. The P. falciparum genome encodes 10 aspartic proteases called plasmepsins, which are involved in diverse cellular processes. Most have been studied extensively but the functions of plasmepsins IX and...
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| Format: | Article |
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American Association for the Advancement of Science (AAAS)
2018
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| Online Access: | http://hdl.handle.net/1721.1/118955 https://orcid.org/0000-0002-6250-8796 |
| _version_ | 1811095773706715136 |
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| author | Nasamu, Armiyaw S. Glushakova, Svetlana Russo, Ilaria Vaupel, Barbara Oksman, Anna Kim, Arthur S. Fremont, Daved H. Tolia, Niraj Beck, Josh R. Meyers, Marvin J. Zimmerberg, Joshua Goldberg, Daniel E. Niles, Jacquin |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Nasamu, Armiyaw S. Glushakova, Svetlana Russo, Ilaria Vaupel, Barbara Oksman, Anna Kim, Arthur S. Fremont, Daved H. Tolia, Niraj Beck, Josh R. Meyers, Marvin J. Zimmerberg, Joshua Goldberg, Daniel E. Niles, Jacquin |
| author_sort | Nasamu, Armiyaw S. |
| collection | MIT |
| description | Proteases of the malaria parasite Plasmodium falciparum have long been investigated as drug targets. The P. falciparum genome encodes 10 aspartic proteases called plasmepsins, which are involved in diverse cellular processes. Most have been studied extensively but the functions of plasmepsins IX and X (PMIX and PMX) were unknown. Here we show that PMIX is essential for erythrocyte invasion, acting on rhoptry secretory organelle biogenesis. In contrast, PMX is essential for both egress and invasion, controlling maturation of the subtilisin-like serine protease SUB1 in exoneme secretory vesicles. We have identified compounds with potent antimalarial activity targeting PMX, including a compound known to have oral efficacy in a mouse model of malaria. |
| first_indexed | 2024-09-23T16:27:22Z |
| format | Article |
| id | mit-1721.1/118955 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T16:27:22Z |
| publishDate | 2018 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1189552022-09-29T19:53:21Z Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion Nasamu, Armiyaw S. Glushakova, Svetlana Russo, Ilaria Vaupel, Barbara Oksman, Anna Kim, Arthur S. Fremont, Daved H. Tolia, Niraj Beck, Josh R. Meyers, Marvin J. Zimmerberg, Joshua Goldberg, Daniel E. Niles, Jacquin Massachusetts Institute of Technology. Department of Biological Engineering Niles, Jacquin Proteases of the malaria parasite Plasmodium falciparum have long been investigated as drug targets. The P. falciparum genome encodes 10 aspartic proteases called plasmepsins, which are involved in diverse cellular processes. Most have been studied extensively but the functions of plasmepsins IX and X (PMIX and PMX) were unknown. Here we show that PMIX is essential for erythrocyte invasion, acting on rhoptry secretory organelle biogenesis. In contrast, PMX is essential for both egress and invasion, controlling maturation of the subtilisin-like serine protease SUB1 in exoneme secretory vesicles. We have identified compounds with potent antimalarial activity targeting PMX, including a compound known to have oral efficacy in a mouse model of malaria. 2018-11-08T15:35:56Z 2018-11-08T15:35:56Z 2017-10 2017-03 2018-11-06T14:20:50Z Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/118955 Nasamu, Armiyaw S. et al. “Plasmepsins IX and X Are Essential and Druggable Mediators of Malaria Parasite Egress and Invasion.” Science 358, 6362 (October 2017): 518–522 © 2017 The Authors https://orcid.org/0000-0002-6250-8796 http://dx.doi.org/10.1126/SCIENCE.AAN1478 Science Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Nasamu, Armiyaw S. Glushakova, Svetlana Russo, Ilaria Vaupel, Barbara Oksman, Anna Kim, Arthur S. Fremont, Daved H. Tolia, Niraj Beck, Josh R. Meyers, Marvin J. Zimmerberg, Joshua Goldberg, Daniel E. Niles, Jacquin Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion |
| title | Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion |
| title_full | Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion |
| title_fullStr | Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion |
| title_full_unstemmed | Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion |
| title_short | Plasmepsins IX and X are essential and druggable mediators of malaria parasite egress and invasion |
| title_sort | plasmepsins ix and x are essential and druggable mediators of malaria parasite egress and invasion |
| url | http://hdl.handle.net/1721.1/118955 https://orcid.org/0000-0002-6250-8796 |
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