濡木研公開ラボセミナー
Identification of anti-dengue from marine organisms
Sarin Chimnaronk, Ph.D.（Institute of Molecular Biosciences, Mahidol University, Thailand）
2023年12月04日(月) 16:00-17:00 理学部1号館中央棟341号室
The four serotypes of dengue virus (DENV) infect 390 million people causing over 20,000 deaths annually worldwide. Currently, no effective prevention and therapeutic drug is available. The DENV non-structural protein 5 (NS5) is an attractive target for drug development because it contains the RNA-dependent RNA polymerase (RdRp) activity and the stem-loop (SL) RNA promoter-binding activity, both of which are indispensable for the de novo synthesis of viral RNA. In this study, we performed robust screening and identified a novel chemotype from marine species that synchronously targeted two RdRp activities. We found that lissoclibadin 4 effectively interfered with SL’s access to RdRp and inhibited DENV replication and production in human hepatic cells for all serotypes with IC50 values of 2–4 μM. Notably, lissoclibadin 4 also inhibited the polymerization activity via a covalent interaction with the conserved Cys709 residue, which triggered the rearrangement of the priming loop of RdRp. Characterization of lissoclibadin 4 derivatives revealed that the presence of an intramolecular disulfide and one dopamine group is crucial for the anti-DENV activity. Our results rendered a novel pan-serotype lead type with dual-affinity to DENV RdRp, which should reduce the chance of escape mutations.
担当：東京大学大学院理学系研究科・生物科学専攻・濡木理
※学内限定
