Functional Studies of Plasmodium falciparum Dipeptidyl Aminopeptidase I Using Small Molecule Inhibitors and Active Site Probes
| Autor: | Jonathan A. Ellman, Matthew Bogyo, Edgar Deu, Mark J. Rice, Melissa J. Leyva, Victoria E. Albrow |
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| Rok vydání: | 2010 |
| Předmět: |
Drug
MICROBIO media_common.quotation_subject Clinical Biochemistry Biology Pharmacology 01 natural sciences Biochemistry Cathepsin C 03 medical and health sciences Drug Discovery medicine Parasite hosting Molecular Biology 030304 developmental biology media_common chemistry.chemical_classification 0303 health sciences 010405 organic chemistry Plasmodium falciparum General Medicine biology.organism_classification medicine.disease Small molecule Antiparasitic agent 3. Good health 0104 chemical sciences CHEMBIO Enzyme chemistry Molecular Medicine Malaria |
| Zdroj: | Chemistry & Biology. 17(8):808-819 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2010.06.007 |
| Popis: | SummaryThe 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. |
| Databáze: | OpenAIRE |
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