6J00

The RNA-dependent RNA polymerase domain of dengue 3 NS5

Summary for 6J00

• Entry DOI: 10.2210/pdb6j00/pdb
• Descriptor: Genome polyprotein, ZINC ION (3 entities in total)
• Functional Keywords: dengue, ns5, rna-dependent rna polymerase, viral protein
• Biological source: Dengue virus 3
• Total number of polymer chains: 1
• Total formula weight: 74929.81

Authors

Shimizu, H.,Sekine, S. (deposition date: 2018-12-20, release date: 2019-12-25, Last modification date: 2023-11-22)

Primary citation

Shimizu, H.,Saito, A.,Mikuni, J.,Nakayama, E.E.,Koyama, H.,Honma, T.,Shirouzu, M.,Sekine, S.I.,Shioda, T.
Discovery of a small molecule inhibitor targeting dengue virus NS5 RNA-dependent RNA polymerase.
Plos Negl Trop Dis, 13:e0007894-e0007894, 2019

PubMed Abstract: Dengue 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 μM 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.

PubMed: 31738758
DOI: 10.1371/journal.pntd.0007894

Experimental method

X-RAY DIFFRACTION (2.14 Å)