Identification of Plasmodium dipeptidyl aminopeptidase allosteric inhibitors by high throughput screening


Autoři: Mateo I. Sanchez aff001;  Laura E. de Vries aff002;  Christine Lehmann aff002;  Jeong T. Lee aff001;  Kenny K. Ang aff003;  Christopher Wilson aff003;  Steven Chen aff003;  Michelle R. Arkin aff003;  Matthew Bogyo aff001;  Edgar Deu aff002
Působiště autorů: Departments of Pathology and Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, United States of America aff001;  Chemical Biology Approaches to Malaria Lab, The Francis Crick Institute, London, United Kingdom aff002;  Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226270

Souhrn

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.

Klíčová slova:

Antimalarials – Enzyme inhibitors – Malaria – Malarial parasites – Parasitic diseases – Plasmodium – Proteases – Parasite replication


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2019 Číslo 12