Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18
Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial ac- tivity, but not necessa...
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| Format: | Article |
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Public Library of Science
2015
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| Online Access: | https://eprints.nottingham.ac.uk/30309/ |
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| author | Paiardini, Alessandro Bamert, Rebecca S. Kannan-Sivaraman, Komagal Drinkwater, Nyssa Mistry, Shailesh N. Scammells, Peter J. McGowan, Sheena |
| author_facet | Paiardini, Alessandro Bamert, Rebecca S. Kannan-Sivaraman, Komagal Drinkwater, Nyssa Mistry, Shailesh N. Scammells, Peter J. McGowan, Sheena |
| author_sort | Paiardini, Alessandro |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial ac- tivity, but not necessarily the molecular targets. In this study, we assess the ability of the “MMV 400” compounds to inhibit the activity of three metalloaminopeptidases from Plasmo- dium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopepti- dases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopepti- dases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordina- tion or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA- M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity re- ported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors uti- lising non-classical zinc binding groups. |
| first_indexed | 2025-11-14T19:08:36Z |
| format | Article |
| id | nottingham-30309 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:08:36Z |
| publishDate | 2015 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-303092020-05-04T17:02:20Z https://eprints.nottingham.ac.uk/30309/ Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 Paiardini, Alessandro Bamert, Rebecca S. Kannan-Sivaraman, Komagal Drinkwater, Nyssa Mistry, Shailesh N. Scammells, Peter J. McGowan, Sheena Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial ac- tivity, but not necessarily the molecular targets. In this study, we assess the ability of the “MMV 400” compounds to inhibit the activity of three metalloaminopeptidases from Plasmo- dium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopepti- dases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopepti- dases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordina- tion or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA- M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity re- ported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors uti- lising non-classical zinc binding groups. Public Library of Science 2015-02-20 Article PeerReviewed Paiardini, Alessandro, Bamert, Rebecca S., Kannan-Sivaraman, Komagal, Drinkwater, Nyssa, Mistry, Shailesh N., Scammells, Peter J. and McGowan, Sheena (2015) Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18. PLoS ONE, 10 (2). e0115859/1-e0115859/14. ISSN 1932-6203 malaria Plasmodium antimalerial aminopeptidases http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115859 doi:10.1371/journal.pone.0115859 doi:10.1371/journal.pone.0115859 |
| spellingShingle | malaria Plasmodium antimalerial aminopeptidases Paiardini, Alessandro Bamert, Rebecca S. Kannan-Sivaraman, Komagal Drinkwater, Nyssa Mistry, Shailesh N. Scammells, Peter J. McGowan, Sheena Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 |
| title | Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 |
| title_full | Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 |
| title_fullStr | Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 |
| title_full_unstemmed | Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 |
| title_short | Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18 |
| title_sort | screening the medicines for malaria venture "malaria box" against the plasmodium falciparum aminopeptidases, m1, m17 and m18 |
| topic | malaria Plasmodium antimalerial aminopeptidases |
| url | https://eprints.nottingham.ac.uk/30309/ https://eprints.nottingham.ac.uk/30309/ https://eprints.nottingham.ac.uk/30309/ |