Exploration of the P region of PEXEL peptidomimetics leads to a potent inhibitor of the Plasmodium protease, plasmepsin V
- Author(s)
- Gazdik, M; Jarman, KE; O'Neill, MT; Hodder, AN; Lowes, KN; Jousset Sabroux, H; Cowman, AF; Boddey, JA; Sleebs, BE;
- Details
- Publication Year 2016-05-01,Volume 24,Issue #9,Page 1993-2010
- Journal Title
- Bioorg Med Chem
- Publication Type
- Journal Article
- Abstract
- The use of arginine isosteres is a known strategy to overcome poor membrane permeability commonly associated with peptides or peptidomimetics that possess this highly polar amino acid. Here, we apply this strategy to peptidomimetics that are potent inhibitors of the malarial protease, plasmepsin V, with the aim of enhancing their activity against Plasmodium parasites, and exploring the structure-activity relationship of the P3 arginine within the S3 pocket of plasmepsin V. Of the arginine isosteres trialled in the P3 position, we discovered that canavanine was the ideal and that this peptidomimetic potently inhibits plasmepsin V, efficiently blocks protein export and inhibits parasite growth. Structure studies of the peptidomimetics bound to plasmepsin V provided insight into the structural basis for the enzyme activity observed in vitro and provides further evidence why plasmepsin V is highly sensitive to substrate modification.
- Publisher
- Elsevier
- Research Division(s)
- Chemical Biology; Systems Biology And Personalised Medicine; Infection And Immunity
- PubMed ID
- 27021426
- Publisher's Version
- https://doi.org/10.1016/j.bmc.2016.03.027
- NHMRC Grants
- NHMRC/1010326, NHMRC/1092789,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-04-05 01:43:54
Last Modified: 2016-05-09 12:37:51