期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2022696118
关键词
serine protease; boronic acid; egress; Plasmodium falciparum; malaria
资金
- Wellcome Trust [106239/Z/14/A, FC001043]
- Francis Crick Institute
- Cancer Research United Kingdom [FC001043]
- UK Medical Research Council [FC001043]
- European Regional Development Fund [1.1.1.1/16/A/290]
- Wellcome ISSF2
- Wellcome Trust [106239/Z/14/A] Funding Source: Wellcome Trust
Malaria is a devastating infectious disease causing over 400,000 deaths annually. Researchers have developed substrate-based peptidic boronic acids that inhibit a parasite protease called SUB1, preventing parasite replication through egress and potentially serving as a new class of antimalarial drugs.
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 membranepermeable, 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.
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