Abstract
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.
Highlights
Malaria, a disease caused by obligate intracellular parasites of the genus Plasmodium, is a global health problem threatening more than half the earth’s population [1]
We have previously reported the rational design of peptidic ketoamide inhibitors of P. falciparum SUB1 (PfSUB1) based on the substrate specificity of the enzyme (Fig. 1) [13, 20]
We previously described the development of a fluorescence-based in vitro assay suitable for the evaluation of substrate-based PfSUB1 inhibitors, using recombinant PfSUB1 and fluorogenic peptide substrates based on cleavage sites within endogenous protein substrates of PfSUB1 [13, 21]
Summary
A disease caused by obligate intracellular parasites of the genus Plasmodium, is a global health problem threatening more than half the earth’s population [1]. Clinical malaria results from repeated rounds of replication of the parasite in circulating red blood cells (RBCs). Merozoites invade the cells and divide asexually within a membrane-bound parasitophorous vacuole (PV) to produce a mature multinucleated form called a schizont. This undergoes segmentation to generate 16 or more daughter merozoites, which are eventually released through a lytic process called egress, in the process destroying the infected RBC. Escape from the red cell, a process called egress, involves a proteolytic pathway triggered by an essential parasite subtilisin-like serine protease called SUB1. We describe the development and rational optimization of a potent, membrane-permeable substrate-based boronic acid compounds that block egress and parasite proliferation by direct inhibition of SUB1 activity. These efforts have generated nanomolar PfSUB1 inhibitors that can access PfSUB1 in the intraerythrocytic parasite and prevent parasite replication through direct inhibition of egress
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