Novel broad-spectrum activity-based probes to profile malarial cysteine proteases
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Le résumé fourni par la source
Clan CA cysteine proteases, also known as papain-like proteases, play important roles throughout the malaria parasite life cycle and are therefore potential drug targets to treat this disease and prevent its transmission. In order to study the biological function of these proteases and to chemically validate some of them as viable drug targets, highly specific inhibitors need to be developed. This is especially challenging given the large number of clan CA proteases present in Plasmodium species (ten in Plasmodium falciparum), and the difficulty of designing selective inhibitors that do not cross-react with other members of the same family. Additionally, any efforts to develop antimalarial drugs targeting these proteases will also have to take into account potential off-target effects against the 11 human cysteine cathepsins. Activity-based protein profiling has been a very useful tool to determine the specificity of inhibitors against all members of an enzyme family. However, current clan CA proteases broad-spectrum activity-based probes either target endopeptidases or dipeptidyl aminopeptidases, but not both subfamilies efficiently. In this study, we present a new series of dipeptydic vinyl sulfone probes containing a free N-terminal tryptophan and a fluorophore at the P1 position that are able to label both subfamilies efficiently, both in Plasmodium falciparum and in mammalian cells, thus making them better broad-spectrum activity-based probes. We also show that some of these probes are cell permeable and can therefore be used to determine the specificity of inhibitors in living cells. Interestingly, we show that the choice of fluorophore greatly influences the specificity of the probes as well as their cell permeability.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Novel broad-spectrum activity-based probes to profile malarial cysteine proteases
- Date Crossref
- 10/01/2020
- Éditeur
- Public Library of Science (PLoS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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The Francis Crick Institute pays non établi dans la noticeStructure de recherche
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Stanford Medicine pays non établi dans la noticeÉtablissement de santé
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The University of Melbourne Department of Biochemistry and Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
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Monash University Monash Institute of Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
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New York University pays non établi dans la noticeUniversité ou école supérieure
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Stanford School of Medicine Department of Genetics pays non établi dans la noticeUniversité ou école supérieure
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College of Dentistry Department of Maxillofacial Surgery pays non établi dans la noticeUniversité ou école supérieure
The Francis Crick Institute, Stanford Medicine et Department of Biochemistry and Molecular Biology — The University of Melbourne, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.