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Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome.

Chrislaine Withers-MartinezElina LidumnieceFiona HackettChristine R CollinsZahie TahaMichael J BlackmanAigars Jirgensons
Published in: Journal of medicinal chemistry (2024)
Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is essential for egress of invasive merozoite forms of the parasite, rendering PfSUB1 an attractive antimalarial target. Here, we report studies aimed to improve drug-like properties of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity and selectivity over human proteasome (H20S). Structure-activity relationship investigations revealed that lipophilic P 3 amino acid side chains as well as N -capping groups were well tolerated in retaining PfSUB1 inhibitory potency. At the P 1 position, replacing the methyl group with a carboxyethyl substituent led to boralactone PfSUB1 inhibitors with remarkably improved selectivity over H20S. Combining lipophilic end-capping groups with the boralactone reduced the selectivity over H20S. However, compound 4c still showed >60-fold selectivity versus H20S and low nanomolar PfSUB1 inhibitory potency. Importantly, this compound inhibited the growth of a genetically modified P. falciparum line expressing reduced levels of PfSUB1 13-fold more efficiently compared to a wild-type parasite line.
Keyphrases
  • plasmodium falciparum
  • endothelial cells
  • wild type
  • induced pluripotent stem cells
  • amino acid
  • structure activity relationship
  • pluripotent stem cells
  • single cell
  • drug induced