Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D.

ABSTRACT: Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This

SUBMITTER: Zogota R 

PROVIDER: S-EPMC6336538 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature