Journal article
The effect of N-methylation on transition state mimetic inhibitors of the Plasmodium protease, plasmepsin v
M Gazdik, MT O'Neill, S Lopaticki, KN Lowes, BJ Smith, AF Cowman, JA Boddey, BE Sleebs
Medchemcomm | ROYAL SOC CHEMISTRY | Published : 2015
DOI: 10.1039/c4md00409d
Abstract
N-Methylation of the N-Cα peptide bond is a known strategy to overcome the liabilities inherently associated with peptide-like molecules. Here, we apply this strategy to transition state mimetics that are potent inhibitors of the malarial protease, plasmepsin V, with the aim of enhancing their activity against Plasmodium parasites. We demonstrate that independent N-methylation of each N-Cα bond of the mimetics interferes with binding interactions to plasmepsin V, resulting in reduced affinity for the protease. We provide evidence that N-methylation improves proteolytic stability and slightly improves lipophilicity. However, the observed parasite activity of the N-methyl compounds had little ..
View full abstractGrants
Awarded by National Health and Medical Research Council of Australia
Awarded by CASS Foundation Science and Medicine grant
Funding Acknowledgements
This work was funded by the National Health and Medical Research Council of Australia (Project Grant 1010326 to J.A.B), a CASS Foundation Science and Medicine grant (SM.12.4348 to JAB), the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank the University of Melbourne for the provision of an Australian Postgraduate Award to M.G. A.F.C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC. J.A.B is an Australian Research Council QEII Fellow. We thank Guillaume Lessene, Janet Weinstock and Andrew Powell for useful discussions.