Functional Studies of Plasmodium falciparum Dipeptidyl Aminopeptidase I Using Small Molecule Inhibitors and Active Site Probes

摘要: The widespread resistance of malaria parasites to all affordable drugs has made the identification new targets urgent. Dipeptidyl aminopeptidases (DPAPs) represent potentially valuable that are involved in hemoglobin degradation (DPAP1) and parasite egress (DPAP3). Here we use activity-based probes demonstrate specific inhibition DPAP1 by a small molecule results formation an immature trophozoite leads death. Using computational methods, designed stable, nonpeptidic covalent inhibitors kill Plasmodium falciparum at low nanomolar concentrations. These compounds show signs slowing growth murine model malaria, which suggests might be viable antimalarial target. Interestingly, found resynthesis activation after is rapid, suggesting effective would need sustain for period 2-3 hr.