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Peptidic boronic acids are potent cell-permeable inhibitors of the malaria parasite egress serine protease SUB1.

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journal contribution
posted on 18.05.2021, 16:27 by Elina Lidumniece, Chrislaine Withers-Martinez, Fiona Hackett, Christine R Collins, Abigail J Perrin, Konstantinos Koussis, Claudine Bisson, Michael J Blackman, Aigars Jirgensons
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.

Funding

Crick (Grant ID: 10043, Grant title: Blackman FC001043) Wellcome Trust (Grant ID: 106239/Z/14/A, Grant title: WT 106239/Z/14/A)

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