1. Novel Inhibitors of Severe Acute Respiratory Syndrome Coronavirus Entry That Act by Three Distinct Mechanisms.
- Author
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Adedeji, Adeyemi O., Severson, William, Jonsson, Colleen, Singh, Kamalendra, Weiss, Susan R., and Sarafianos, Stefan G.
- Subjects
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SARS disease , *CORONAVIRUSES , *MEMBRANE glycoproteins , *COMMUNICABLE diseases , *CARBOXAMIDES , *VIRAL envelopes - 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 discov-ered by screening a chemical library of compounds for blocking of entry of HIV-1 pseudotyped with SARS-CoV surface glyco-protein S (SARS-S) but not that of HIV-1 pseudotyped with vesicular stomatitis virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that the compounds act by three distinct mechanisms: (i) SSAA09E2 {¿V-[[4-(4-methyl-piperazin-l-yl)phenyl]methyl]-l,2-oxazole-5-carboxamide} acts through a novel mechanism of action, by blocking early interac-tions of SARS-S with the receptor for SARS-CoV, angiotensin converting enzyme 2 (ACE2); (ii) SSAA09E1 {[(Z)-l-thiophen-2-ylethylideneamino] thiourea} acts later, by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry; and (iii) SSAA09E3 [¿V-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide] 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 for blocking SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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