Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors
Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. T...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Chemical Society
2014
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| Online Access: | https://eprints.nottingham.ac.uk/30311/ |
| _version_ | 1848793961139798016 |
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| author | Mistry, Shailesh N. Drinkwater, Nyssa Ruggeri, Chiara Sivaraman, Komagal Kannan Loganathan, Sasdekumar Fletcher, Sabine Drag, Marcin Paiardini, Alessandro Avery, Vicky M. Scammells, Peter J. McGowan, Sheena |
| author_facet | Mistry, Shailesh N. Drinkwater, Nyssa Ruggeri, Chiara Sivaraman, Komagal Kannan Loganathan, Sasdekumar Fletcher, Sabine Drag, Marcin Paiardini, Alessandro Avery, Vicky M. Scammells, Peter J. McGowan, Sheena |
| author_sort | Mistry, Shailesh N. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics. |
| first_indexed | 2025-11-14T19:08:37Z |
| format | Article |
| id | nottingham-30311 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T19:08:37Z |
| publishDate | 2014 |
| publisher | American Chemical Society |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-303112020-05-08T12:45:11Z https://eprints.nottingham.ac.uk/30311/ Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors Mistry, Shailesh N. Drinkwater, Nyssa Ruggeri, Chiara Sivaraman, Komagal Kannan Loganathan, Sasdekumar Fletcher, Sabine Drag, Marcin Paiardini, Alessandro Avery, Vicky M. Scammells, Peter J. McGowan, Sheena Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics. American Chemical Society 2014-10-24 Article PeerReviewed application/pdf en https://eprints.nottingham.ac.uk/30311/1/jm-2014-01323a.R1%20-%20JMC%2057%2821%29%202014%209168.pdf Mistry, Shailesh N., Drinkwater, Nyssa, Ruggeri, Chiara, Sivaraman, Komagal Kannan, Loganathan, Sasdekumar, Fletcher, Sabine, Drag, Marcin, Paiardini, Alessandro, Avery, Vicky M., Scammells, Peter J. and McGowan, Sheena (2014) Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors. Journal of Medicinal Chemistry, 57 (21). pp. 9168-9183. ISSN 0022-2623 http://pubs.acs.org/doi/abs/10.1021/jm501323a doi:10.1021/jm501323a doi:10.1021/jm501323a |
| spellingShingle | Mistry, Shailesh N. Drinkwater, Nyssa Ruggeri, Chiara Sivaraman, Komagal Kannan Loganathan, Sasdekumar Fletcher, Sabine Drag, Marcin Paiardini, Alessandro Avery, Vicky M. Scammells, Peter J. McGowan, Sheena Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| title | Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| title_full | Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| title_fullStr | Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| title_full_unstemmed | Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| title_short | Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| title_sort | two-pronged attack: dual inhibition of plasmodium falciparum m1 and m17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors |
| url | https://eprints.nottingham.ac.uk/30311/ https://eprints.nottingham.ac.uk/30311/ https://eprints.nottingham.ac.uk/30311/ |