Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease SUB1.
Lidumniece, Elina;
Withers-Martinez, Chrislaine;
Hackett, Fiona;
Collins, Christine R;
Perrin, Abigail J;
Koussis, Konstantinos;
Bisson, Claudine;
Blackman, Michael J;
Jirgensons, Aigars;
(2021)
Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease SUB1.
Proceedings of the National Academy of Sciences of the United States of America, 118 (20).
e2022696118-e2022696118.
ISSN 0027-8424
DOI: https://doi.org/10.1073/pnas.2022696118
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Malaria is a devastating infectious disease, which causes over 400,000 deaths per annum and impacts the lives of nearly half the world's population. The causative agent, a protozoan parasite, replicates within red blood cells (RBCs), eventually destroying the cells in a lytic process called egress to release a new generation of parasites. These invade fresh RBCs to repeat the cycle. Egress is regulated by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and optimization of substrate-based peptidic boronic acids that inhibit Plasmodium falciparum SUB1 with low nanomolar potency. Structural optimization generated membrane-permeable, slow off-rate inhibitors that prevent Pfalciparum egress through direct inhibition of SUB1 activity and block parasite replication in vitro at submicromolar concentrations. Our results validate SUB1 as a potential target for a new class of antimalarial drugs designed to prevent parasite replication and disease progression.