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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2010-7-15
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pubmed:abstractText |
A tetrahydroquinoline oxocarbazate (PubChem CID 23631927) was tested as an inhibitor of human cathepsin L (EC 3.4.22.15) and as an entry blocker of severe acute respiratory syndrome (SARS) coronavirus and Ebola pseudotype virus. In the cathepsin L inhibition assay, the oxocarbazate caused a time-dependent 17-fold drop in IC(50) from 6.9 nM (no preincubation) to 0.4 nM (4-h preincubation). Slowly reversible inhibition was demonstrated in a dilution assay. A transient kinetic analysis using a single-step competitive inhibition model provided rate constants of k(on) = 153,000 M(-1)s(-1) and k(off) = 4.40 x 10(-5) s(-1) (K(i) = 0.29 nM). The compound also displayed cathepsin L/B selectivity of >700-fold and was nontoxic to human aortic endothelial cells at 100 muM. The oxocarbazate and a related thiocarbazate (PubChem CID 16725315) were tested in a SARS coronavirus (CoV) and Ebola virus-pseudotype infection assay with the oxocarbazate but not the thiocarbazate, demonstrating activity in blocking both SARS-CoV (IC(50) = 273 +/- 49 nM) and Ebola virus (IC(50) = 193 +/- 39 nM) entry into human embryonic kidney 293T cells. To trace the intracellular action of the inhibitors with intracellular cathepsin L, the activity-based probe biotin-Lys-C5 alkyl linker-Tyr-Leu-epoxide (DCG-04) was used to label the active site of cysteine proteases in 293T lysates. The reduction in active cathepsin L in inhibitor-treated cells correlated well with the observed potency of inhibitors observed in the virus pseudotype infection assay. Overall, the oxocarbazate CID 23631927 was a subnanomolar, slow-binding, reversible inhibitor of human cathepsin L that blocked SARS-CoV and Ebola pseudotype virus entry in human cells.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-10410800,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-11048948,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-11532926,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-12471262,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-18060772,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-18403718,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-18499453,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/20466822-9074757
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1521-0111
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pubmed:author |
pubmed-author:BatesPaulP,
pubmed-author:DiamondScott LSL,
pubmed-author:GreenbaumDoron CDC,
pubmed-author:HurynDonna MDM,
pubmed-author:JingHuiyanH,
pubmed-author:KaletskyRachel LRL,
pubmed-author:MyersMichael CMC,
pubmed-author:PurvisJeremy EJE,
pubmed-author:ShahParag PPP,
pubmed-author:SmithAmos BAB3rd,
pubmed-author:WangTianhuaT
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pubmed:issnType |
Electronic
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pubmed:volume |
78
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
319-24
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pubmed:dateRevised |
2011-8-3
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pubmed:meshHeading |
pubmed-meshheading:20466822-Antiviral Agents,
pubmed-meshheading:20466822-Cathepsin L,
pubmed-meshheading:20466822-Cell Line,
pubmed-meshheading:20466822-Cysteine Proteinase Inhibitors,
pubmed-meshheading:20466822-Hemorrhagic Fever, Ebola,
pubmed-meshheading:20466822-Humans,
pubmed-meshheading:20466822-Kinetics,
pubmed-meshheading:20466822-Quinolines,
pubmed-meshheading:20466822-Quinolones,
pubmed-meshheading:20466822-Severe Acute Respiratory Syndrome
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pubmed:year |
2010
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pubmed:articleTitle |
A small-molecule oxocarbazate inhibitor of human cathepsin L blocks severe acute respiratory syndrome and ebola pseudotype virus infection into human embryonic kidney 293T cells.
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pubmed:affiliation |
Department of Chemical and Biomolecular Engineering, Penn Center for Molecular Discovery, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6383, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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