Issue 3, 2015
From the journal:

MedChemComm

The effect of N-methylation on transition state mimetic inhibitors of the Plasmodium protease, plasmepsin V†

Michelle Gazdik,ab   Matthew T. O'Neill,ab   Sash Lopaticki,ab   Kym N. Lowes,ab   Brian J. Smith,c   Alan F. Cowman,ab   Justin A. Boddeyab  and  Brad E. Sleebs*ab  

* Corresponding authors

a The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
E-mail: sleebs@wehi.edu.au
Tel: +61 3 9345 2718

b Department of Medical Biology, The University of Melbourne, Parkville, Australia

c Department of Chemistry, La Trobe University, Australia

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 correlation with on-target plasmepsin V activity, indicating non-specific activity. This study underscores the benefits and the drawbacks of the N-methylation strategy, and provides further evidence that plasmepsin V is highly sensitive to substrate modification.

Graphical abstract: The effect of N-methylation on transition state mimetic inhibitors of the Plasmodium protease, plasmepsin V

About
Cited by
Related
Download options Please wait...

Supplementary files

Article information

DOI
https://doi.org/10.1039/C4MD00409D
Article type
Concise Article
Submitted
15 Sep 2014
Accepted
24 Nov 2014
First published
25 Nov 2014

Med. Chem. Commun., 2015,6, 437-443

Permissions

Request permissions

The effect of N-methylation on transition state mimetic inhibitors of the Plasmodium protease, plasmepsin V

M. Gazdik, M. T. O'Neill, S. Lopaticki, K. N. Lowes, B. J. Smith, A. F. Cowman, J. A. Boddey and B. E. Sleebs, Med. Chem. Commun., 2015, 6, 437 DOI: 10.1039/C4MD00409D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements