6izy | pdb_00006izy
The RNA-dependent RNA polymerase domain of dengue 2 NS5
Structural highlights
Publication Abstract from PubMedDengue is a mosquito-borne viral infection that has spread globally in recent years. Around half of the world's population, especially in the tropics and subtropics, is at risk of infection. Every year, 50-100 million clinical cases are reported, and more than 500,000 patients develop the symptoms of severe dengue infection: dengue haemorrhagic fever and dengue shock syndrome, which threaten life in Asia and Latin America. No antiviral drug for dengue is available. The dengue virus (DENV) non-structural protein 5 (NS5), which possesses the RNA-dependent RNA polymerase (RdRp) activity and is responsible for viral replication and transcription, is an attractive target for anti-dengue drug development. In the present study, 16,240 small-molecule compounds in a fragment library were screened for their capabilities to inhibit the DENV type 2 (DENV2) RdRp activities in vitro. Based on in cellulo antiviral and cytotoxity assays, we selected the compound RK-0404678 with the EC50 value of 6.0 muM for DENV2. Crystallographic analyses revealed two unique binding sites for RK-0404678 within the RdRp, which are conserved in flavivirus NS5 proteins. No resistant viruses emerged after nine rounds of serial passage of DENV2 in the presence of RK-0404678, suggesting the high genetic barrier of this compound to the emergence of a resistant virus. Collectively, RK-0404678 and its binding sites provide a new framework for antiviral drug development. Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase.,Shimizu H, Saito A, Mikuni J, Nakayama EE, Koyama H, Honma T, Shirouzu M, Sekine SI, Shioda T PLoS Negl Trop Dis. 2019 Nov 18;13(11):e0007894. doi:, 10.1371/journal.pntd.0007894. eCollection 2019 Nov. PMID:31738758[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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