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Psammaplin A inhibits hepatitis C virus NS3 helicase

Author:
Salam, Kazi Abdus, Furuta, Atsushi, Noda, Naohiro, Tsuneda, Satoshi, Sekiguchi, Yuji, Yamashita, Atsuya, Moriishi, Kohji, Nakakoshi, Masamichi, Tsubuki, Masayoshi, Tani, Hidenori, Tanaka, Junichi, Akimitsu, Nobuyoshi
Source:
Natural medicines 2013 v.67 no.4 pp. 765-772
ISSN:
1340-3443
Subject:
Hepatitis C virus, RNA, RNA helicases, adenosinetriphosphatase, electron transfer, genotype, hepatitis C, hepatoma, inhibitory concentration 50, nucleoside-triphosphate phosphatase, replicon, screening, virus replication
Abstract:
Hepatitis C virus (HCV) is the causative agent of hepatitis C, a chronic infectious disease that can lead to development of hepatocellular carcinoma. The NS3 nucleoside triphosphatase (NTPase)/helicase has an essential role in HCV replication, and is therefore an attractive target for direct-acting antiviral strategies. In this study, we employed high-throughput screening using a photo-induced electron transfer (PET) system to identify an inhibitor of NS3 helicase from marine organism extracts. We successfully identified psammaplin A as a novel NS3 inhibitor. The dose–response relationship clearly demonstrates the inhibition of NS3 RNA helicase and ATPase activities by psammaplin A, with IC₅₀values of 17 and 32 μM, respectively. Psammaplin A has no influence on the apparent Kₘvalue (0.4 mM) of NS3 ATPase activity, and acts as a non-competitive inhibitor. Additionally, it inhibits the binding of NS3 to single-stranded RNA in a dose-dependent manner. Furthermore, psammaplin A shows an inhibitory effect on viral replication, with EC₅₀values of 6.1 and 6.3 μM in subgenomic replicon cells derived from genotypes 1b and 2a, respectively. We postulate that psammaplin A is a potential anti-viral agent through the inhibition of ATPase, RNA binding and helicase activities of NS3.
Agid:
228968