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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

Authors

Nyssa Drinkwater

Chiara Ruggeri

Komagal Kannan Sivaraman

Sasdekumar Loganathan

Sabine Fletcher

Marcin Drag

Alessandro Paiardini

Vicky M. Avery

Peter J. Scammells

Sheena McGowan



Abstract

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.

Journal Article Type Article
Publication Date Oct 9, 2014
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 57
Issue 21
APA6 Citation Mistry, S. N., Drinkwater, N., Ruggeri, C., Sivaraman, K. K., Loganathan, S., Fletcher, S., …McGowan, S. (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), doi:10.1021/jm501323a
DOI https://doi.org/10.1021/jm501323a
Publisher URL http://pubs.acs.org/doi/abs/10.1021/jm501323a
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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