Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome
Journal of Medicinal Chemistry 2024
Chrislaine Withers-Martinez, Elīna Līdumniece, Fiona Hackett, Christine R Collins, Zahie Taha, Michael J Blackman, Aigars Jirgensons

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 P3 amino acid side chains as well as N-capping groups were well tolerated in retaining PfSUB1 inhibitory potency. At the P1 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.


Keywords
Chromatography, Ethyl groups, Inhibitors, Parasites, Peptides and proteins
DOI
10.1021/acs.jmedchem.4c01005
Hyperlink
https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01005

Withers-Martinez, C., Līdumniece, E., Hackett, F., Collins, C., Taha, Z., Blackman, M., Jirgensons, A. Peptidic Boronic Acid Plasmodium falciparum SUB1 Inhibitors with Improved Selectivity over Human Proteasome. Journal of Medicinal Chemistry, 2024, Vol. 67, No. 15, pp.13033-13055. ISSN 0022-2623. Available from: doi:10.1021/acs.jmedchem.4c01005

Publication language
English (en)
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