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J Virol. Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms.

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  • J Virol. Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms.

    [Source: US National Library of Medicine, full text: (LINK). Abstract, edited.]
    J Virol. 2013 May 15. [Epub ahead of print]

    Novel Inhibitors of SARS-CoV Entry acting by Three Distinct Mechanisms.

    Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG.


    Source: Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri, 65211.


    Abstract

    Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus, (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of small molecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking entry of HIV-1 pseudotyped with SARS-CoV surface glycoprotein S (SARS-S), but not with Vesicular Stomatitis Virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that they act by three distinct mechanisms: a) SSAA09E2 (N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) acts through a novel mechanism of action, by blocking early interactions of SARS-S with the receptor for SARS-CoV, Angiotensin Converting Enzyme-2 (ACE2); b) SSAA09E1 ([(Z)-1-thiophen-2-ylethylideneamino]thiourea), which acts later by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry and c) SSAA09E3 (N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide)), which also acts later and does not affect interactions of SARS-S with ACE2 or the enzymatic functions of cathepsin L, but prevents fusion of the viral membrane with the host cellular membrane. Our work demonstrates that there are at least three independent strategies to block SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics.


    PMID: 23678171 [PubMed - as supplied by publisher]
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