Functional studies of Plasmodium falciparum dipeptidyl aminopeptidase I using small molecule inhibitors and active site probes.
The widespread resistance of malaria parasites to all affordable drugs has made the identification of new targets urgent. Dipeptidyl aminopeptidases (DPAPs) represent potentially valuable new targets that are involved in hemoglobin degradation (DPAP1) and parasite egress (DPAP3). Here we use activity-based probes to demonstrate that specific inhibition of DPAP1 by a small molecule results in the formation of an immature trophozoite that leads to parasite death. Using computational methods, we designed stable, nonpeptidic covalent inhibitors that kill Plasmodium falciparum at low nanomolar concentrations. These compounds show signs of slowing parasite growth in a murine model of malaria, which suggests that DPAP1 might be a viable antimalarial target. Interestingly, we found that resynthesis and activation of DPAP1 after inhibition is rapid, suggesting that effective drugs would need to sustain DPAP1 inhibition for a period of 2-3 hr.
Deu
Edgar
E
Department of Pathology, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Leyva
Melissa J
MJ
Albrow
Victoria E
VE
Rice
Mark J
MJ
Ellman
Jonathan A
JA
Bogyo
Matthew
M
D000818:Animals; D000977:Antiparasitic Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D020134:Catalytic Domain; D020789:Cathepsin C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D019295:Computational Biology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D011480:Protease Inhibitors / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D053058:Trophozoites / Q000187:drug effects
D000977:Antiparasitic Agents; D011480:Protease Inhibitors; D020789:Cathepsin C
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