Identification of Plasmodium dipeptidyl aminopeptidase allosteric inhibitors by high throughput screening
| Autor: | Kenny K. H. Ang, Michelle R. Arkin, Matthew Bogyo, Edgar Deu, Steven Chen, Laura E. de Vries, Mateo I. Sánchez, Christine Lehmann, Jeong T. Lee, Christopher W. Wilson |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Plasmodium Peptidomimetic lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Druggability Drug Evaluation Preclinical Protozoan Proteins Biochemistry Cathepsin C 0302 clinical medicine Cysteine Proteases Medicine and Health Sciences Enzyme Inhibitors Cells Cultured Protozoans Multidisciplinary Cultured biology Malarial Parasites Eukaryota Drugs Proteases Preclinical 3. Good health Enzymes Drug development 030220 oncology & carcinogenesis Medicine Research Article General Science & Technology Cells Science Allosteric regulation Plasmodium falciparum Cysteine Proteinase Inhibitors Parasite Replication 03 medical and health sciences Antimalarials All institutes and research themes of the Radboud University Medical Center Parasite Groups Parasitic Diseases Humans Dipeptidyl-Peptidases and Tripeptidyl-Peptidases Cathepsin Pharmacology Organisms Biology and Life Sciences Proteins biology.organism_classification Tropical Diseases Parasitic Protozoans Malaria 030104 developmental biology Enzymology Drug Evaluation Parasitology Apicomplexa |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 12, p e0226270 (2019) PloS one, vol 14, iss 12 PLoS One, 14 PLoS One, 14, 12 |
| ISSN: | 1932-6203 |
| Popis: | Dipeptidyl aminopeptidases (DPAPs) are cysteine proteases that cleave dipeptides from the N-terminus of protein substrates and have been shown to play important roles in many pathologies including parasitic diseases such as malaria, toxoplasmosis and Chagas's disease. Inhibitors of the mammalian homologue cathepsin C have been used in clinical trials as potential drugs to treat chronic inflammatory disorders, thus proving that these enzymes are druggable. In Plasmodium species, DPAPs play important functions at different stages of parasite development, thus making them potential antimalarial targets. Most DPAP inhibitors developed to date are peptide-based or peptidomimetic competitive inhibitors. Here, we used a high throughput screening approach to identify novel inhibitor scaffolds that block the activity of Plasmodium falciparum DPAP1. Most of the hits identified in this screen also inhibit Plasmodium falciparum DPAP3, cathepsin C, and to a lesser extent other malarial clan CA proteases, indicating that these might be general DPAP inhibitors. Interestingly, our mechanism of inhibition studies indicate that most hits are allosteric inhibitors, which opens a completely new strategy to inhibit these enzymes, study their biological function, and potentially develop new inhibitors as starting points for drug development. |
| Databáze: | OpenAIRE |
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