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 P. falciparum 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.
Widespread resistance to many antimalarial therapies
currently
in use stresses the need for the discovery of new classes of drugs
with new modes of action. The subtilisin-like serine protease SUB1
controls egress of malaria parasites (merozoites) from the parasite-infected
red blood cell. As such, SUB1 is considered a prospective target for
drugs designed to interrupt the asexual blood stage life cycle of
the malaria parasite. Inhibitors of SUB1 have potential as wide-spectrum
antimalarial drugs, as a single orthologue of SUB1 is found in the
genomes of all known Plasmodium species. This mini-perspective
provides a short overview of the function and structure of SUB1 and
summarizes all of the published SUB1 inhibitors. The inhibitors are
classified by the methods of their discovery, including both rational
design and screening.
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