期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 26, 页码 10094-10100出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja1098325
关键词
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资金
- Ministry of Education, Science and Technology [314-2008-1-E00305, 2010-0029358]
- Ministry for Health and Welfare, Republic of Korea [A092006]
- Korea Health Promotion Institute [A092006] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2010-0029358, 2008-314-E00305] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Programmed -1 ribosomal frameshifting (-1 RF) is an essential regulating mechanism of translation used by SARS-CoV (severe acute respiratory syndrome coronavirus) to synthesize the key replicative proteins encoded by two overlapping open reading frames. The integrity of RNA pseudoknot stability and structure in the -1 RF site is important for efficient -1 RF. Thus, small molecules interacting with high affinity and selectivity with the RNA pseudoknot in the -1 RF site of SARS-CoV (SARS-pseudoknot) would disrupt -1 RF and be fatal to viral infectivity and production. To discover ligands for the SARS-pseudoknot by virtual screening, we constructed a 3D structural model of the SARS-pseudoknot and conducted a computational screening of the chemical database. After virtual screening of about 80 000 compounds against the SARS-pseudoknot structure, high-ranked compounds were selected and their activities were examined by in vitro and cell-based -1 RF assay. We successfully identified a novel ligand 43 that dramatically inhibits the -1 RF of SARS-CoV. This antiframeshift agent is an interesting lead for the design of novel antiviral agents against SARS-CoV.
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