A novel flavivirus entry inhibitor, BP34610, discovered through high-throughput screening with dengue reporter viruses.

In this report, we identified a potential small-molecule inhibitor, BP34610, via cell-based high-throughput screening (HTS) of 12,000 compounds using DENV-2 reporter viruses. BP34610 reduced the virus yields of type 2 DENV-infected cells with a 50% effective concentration (EC50) and selectivity index value of 0.48 ± 0.06 μM and 197, respectively. Without detectable cytotoxicity, the compound inhibited not only all four serotypes of DENV but also Japanese encephalitis virus (JEV). Time-of-addition experiments suggested that BP34610 may act at an early stage of DENV virus infection. Sequencing analyses of several individual clones derived from BP34610-resistant viruses revealed a consensus amino acid substitution (S397P) in the N-terminal stem region of the E protein. Introduction of S397P into the DENV reporter viruses conferred an over 14.8-fold EC90 shift for BP34610. Importantly, the combination of BP34610 with a viral replication inhibitor, ribavirin, displayed synergistic enhancement of anti-DENV-2 activity. Our results identify an effective small-molecule inhibitor, BP34610, which likely targets the DENV E protein. BP34610 could be developed as an anti-flavivirus agent in the future.
PMID: 31654671 [PubMed - as supplied by publisher]

Source: Antiviral Research - October 21, 2019 Category: Virology Authors: Yang CC, Hu HS, Lin HM, Wu PS, Wu RH, Tian JN, Wu SH, Tsou LK, Song JS, Chen HW, Chern JH, Chen CT, Yueh A Tags: Antiviral Res Source Type: research