Novel broad-spectrum activity-based probes to profile malarial cysteine proteases


Autoři: Michele S. Y. Tan aff001;  Dara Davison aff001;  Mateo I. Sanchez aff002;  Bethany M. Anderson aff003;  Stephen Howell aff001;  Ambrosius Snijders aff001;  Laura E. Edgington-Mitchell aff003;  Edgar Deu aff001
Působiště autorů: The Francis Crick Institute, London, United Kingdom aff001;  Department of Genetics, Stanford School of Medicine, Stanford, California, United States of America aff002;  Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville Victoria, Australia aff003;  Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia aff004;  Department of Maxillofacial Surgery, College of Dentistry, New York University, New York, New York, United States of America aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0227341

Souhrn

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.

Klíčová slova:

Cysteine – Cysteine proteases – Malaria – Malarial parasites – Parasitic diseases – Plasmodium – Proteases – Merozoites


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