Please use this identifier to cite or link to this item: https://doi.org/10.1002/chem.201103322
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dc.titleDesign, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents
dc.contributor.authorYang, P.-Y.
dc.contributor.authorWang, M.
dc.contributor.authorLi, L.
dc.contributor.authorWu, H.
dc.contributor.authorHe, C.Y.
dc.contributor.authorYao, S.Q.
dc.date.accessioned2014-06-23T05:35:43Z
dc.date.available2014-06-23T05:35:43Z
dc.date.issued2012-05-21
dc.identifier.citationYang, P.-Y., Wang, M., Li, L., Wu, H., He, C.Y., Yao, S.Q. (2012-05-21). Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents. Chemistry - A European Journal 18 (21) : 6528-6541. ScholarBank@NUS Repository. https://doi.org/10.1002/chem.201103322
dc.identifier.issn09476539
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/75873
dc.description.abstractTrypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas disease and African sleeping sickness, respectively. There is an urgent need for the development of new drugs against both diseases due to the lack of adequate cures and emerging drug resistance. One promising strategy for the discovery of small-molecule therapeutics against parasitic diseases has been to target the major cysteine proteases such as cruzain for T. cruzi, and rhodesain/TbCatB for T. brucei. Azadipeptide nitriles belong to a novel class of extremely potent cysteine protease inhibitors against papain-like proteases. We herein report the design, synthesis, and evaluation of a series of azanitrile-containing compounds, most of which were shown to potently inhibit both recombinant cruzain and rhodesain at low nanomolar/picomolar ranges. A strong correlation between the potency of rhodesain inhibition (i.e., target-based screening) and trypanocidal activity (i.e., whole-organism-based screening) of the compounds was observed. To facilitate detailed studies of this important class of inhibitors, selected hit compounds from our screenings were chemically converted into activity-based probes (ABPs), which were subsequently used for in situ proteome profiling and cellular localization studies to further elucidate potential cellular targets (on and off) in both the disease-relevant bloodstream form (BSF) and the insect-residing procyclic form (PCF) of Trypanosoma brucei. Overall, the inhibitors presented herein show great promise as a new class of anti-trypanosome agents, which possess better activities than existing drugs. The activity-based probes generated from this study could also serve as valuable tools for parasite-based proteome profiling studies, as well as bioimaging agents for studies of cellular uptake and distribution of these drug candidates. Our studies therefore provide a good starting point for further development of these azanitrile-containing compounds as potential anti-parasitic agents. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1002/chem.201103322
dc.sourceScopus
dc.subjectazo compounds
dc.subjectclick chemistry
dc.subjectdrug discovery
dc.subjecthigh-throughput screening
dc.subjectproteomics
dc.subjectstructure-activity relationships
dc.typeArticle
dc.contributor.departmentCHEMISTRY
dc.contributor.departmentBIOLOGICAL SCIENCES
dc.description.doi10.1002/chem.201103322
dc.description.sourcetitleChemistry - A European Journal
dc.description.volume18
dc.description.issue21
dc.description.page6528-6541
dc.description.codenCEUJE
dc.identifier.isiut000304045000019
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