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Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P2 position of PEXEL peptidomimetics.
Nguyen, William; Hodder, Anthony N; de Lezongard, Richard Bestel; Czabotar, Peter E; Jarman, Kate E; O'Neill, Matthew T; Thompson, Jennifer K; Jousset Sabroux, Helene; Cowman, Alan F; Boddey, Justin A; Sleebs, Brad E.
Affiliation
  • Nguyen W; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Hodder AN; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • de Lezongard RB; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Czabotar PE; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Jarman KE; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • O'Neill MT; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
  • Thompson JK; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
  • Jousset Sabroux H; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Cowman AF; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Boddey JA; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
  • Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia. Electronic address: sleebs@wehi.edu.au.
Eur J Med Chem ; 154: 182-198, 2018 Jun 25.
Article in En | MEDLINE | ID: mdl-29800827
Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P3 Arg and P1 Leu in binding affinity and selectivity. Here, we investigate the importance of the P2 position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylglycine or phenylglycine in the P2 position are the most potent inhibitors of plasmepsin V that impair processing of the PEXEL motif in exported proteins resulting in death of P. falciparum asexual stage parasites.
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Full text: 1 Collection: 01-internacional Health context: 3_ND Database: MEDLINE Main subject: Plasmodium falciparum / Protease Inhibitors / Aspartic Acid Endopeptidases / Peptidomimetics / Amino Acids / Antimalarials Language: En Journal: Eur J Med Chem Year: 2018 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Health context: 3_ND Database: MEDLINE Main subject: Plasmodium falciparum / Protease Inhibitors / Aspartic Acid Endopeptidases / Peptidomimetics / Amino Acids / Antimalarials Language: En Journal: Eur J Med Chem Year: 2018 Document type: Article