Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D
Rimants Zogota
Linda Kinena
Chrislaine Withers-Martinez
Michael J Blackman
Raitis Bobrovs
Teodors Pantelejevs
Iveta Kanepe-Lapsa
Vita Ozola
Kristaps Jaudzems
Edgars Suna
Aigars Jirgensons
10779/crick.11410167.v1
https://crick.figshare.com/articles/journal_contribution/Peptidomimetic_plasmepsin_inhibitors_with_potent_anti-malarial_activity_and_selectivity_against_cathepsin_D/11410167
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 resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P. falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.
2019-12-19 18:04:35
Cathepsin D
Hydroxyethylamine
Inhibitors
Malaria
Plasmepsins
Plasmodium falciparum
Animals
Antimalarials
Aspartic Acid Endopeptidases
Erythrocytes
Ethylamines
Humans
Peptidomimetics
Protease Inhibitors
Sequence Alignment
Blackman FC001043
0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
0305 Organic Chemistry
Medicinal & Biomolecular Chemistry