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.
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