Identification of rna pseudoknot-binding ligand that inhibits the - 1 ribosomal frameshifting of SARS-coronavirus by structure-based virtual screening

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.