Pyrazolidinone-based peptidomimetic SARS-CoV-2 Mpro inhibitors.

The main protease (Mpro) of SARS-CoV-2 is an attractive drug target for COVID-19 treatment as it plays an integral role in the proliferation of coronavirus. Herein, we describe the investigation of ß- and γ-lactams as electrophilic "warheads" for covalent binding to Cys145 of the Mpro active site. The highest inhibitory activity (IC50 = 45 ± 3 µM) was achieved using a pyrazolidinone warhead attached to the targeting dipeptide. Importantly, the synergy of the warhead and the targeting dipeptide is crucial for the successful inhibition of Mpro.

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

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.

Azole-based non-peptidomimetic plasmepsin inhibitors.

The spread of drug-resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases - plasmepsins (Plms) - are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole-based non-peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino-piperazine inhibitors. The best triazole-based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance-free antimalarial drug targeting the non-digestive Plm IX or X, which are essential for the malaria parasite life cycle.