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  • Title: A quinoline compound inhibits the replication of dengue virus serotypes 1-4 in Vero cells.
    Author: Beesetti H, Tyagi P, Medapi B, Krishna VS, Sriram D, Khanna N, Swaminathan S.
    Journal: Antivir Ther; 2018; 23(5):385-394. PubMed ID: 29583121.
    Abstract:
    BACKGROUND: The global occurrence of dengue, a mosquito-​borne viral disease caused by four distinct dengue viruses (DENV-1, -2, -3 and -4), is reported to have increased approximately 30-fold in the last 50 years, causing approximately 400 million infections a year. A limited use, sub-optimal live attenuated dengue vaccine has become available recently. It is becoming apparent that antibodies to DENVs can promote infection by Zika virus (ZIKV), a related mosquito-borne flavivirus. A drug to treat these flaviviral infections continues to be an unmet public health need. METHODS: We screened an 'in-house' library of approximately 2,000 small molecules for inhibitors of cloned DENV-2 protease. Putative inhibitor binding to DENV-2 protease was analysed by in silico docking. Anti-DENV activity was analysed by monitoring viral antigen synthesis by ELISA, viral RNA synthesis by reverse-transcription​ coupled to real-time polymerase chain reaction and infectious virus production by plaque assay, in DENV-infected Vero cells. RESULTS: A quinoline derivative, BT24, was identified for the first time as a potent inhibitor of the cloned DENV-2 protease (half maximal inhibitory concentration [IC50]=0.5 µM). In silico analysis revealed that BT24 binds to an allosteric site in the vicinity of the active site of DENV-2 protease. Cell-based assays demonstrated that BT24 can inhibit all four DENVs in infected Vero cells. CONCLUSIONS: BT24 is a DENV-2 protease inhibitor which manifests the capacity to inhibit the replication of all four DENVs in cultured cells. It may provide a lead for a pan-DENV inhibitory drug.
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