Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge
Hepatitis C virus (HCV) is an important etiological agent that is responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV nonstructural protein 3 (NS3) helicase is a possible target for novel drug development due to its essential role in viral replica...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2014-01-01
|
| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1660-3397/12/1/462 |
| _version_ | 1828395096645566464 |
|---|---|
| author | Atsushi Furuta Kazi Abdus Salam Idam Hermawan Nobuyoshi Akimitsu Junichi Tanaka Hidenori Tani Atsuya Yamashita Kohji Moriishi Masamichi Nakakoshi Masayoshi Tsubuki Poh Wee Peng Youichi Suzuki Naoki Yamamoto Yuji Sekiguchi Satoshi Tsuneda Naohiro Noda |
| author_facet | Atsushi Furuta Kazi Abdus Salam Idam Hermawan Nobuyoshi Akimitsu Junichi Tanaka Hidenori Tani Atsuya Yamashita Kohji Moriishi Masamichi Nakakoshi Masayoshi Tsubuki Poh Wee Peng Youichi Suzuki Naoki Yamamoto Yuji Sekiguchi Satoshi Tsuneda Naohiro Noda |
| author_sort | Atsushi Furuta |
| collection | DOAJ |
| description | Hepatitis C virus (HCV) is an important etiological agent that is responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV nonstructural protein 3 (NS3) helicase is a possible target for novel drug development due to its essential role in viral replication. In this study, we identified halisulfate 3 (hal3) and suvanine as novel NS3 helicase inhibitors, with IC50 values of 4 and 3 µM, respectively, from a marine sponge by screening extracts of marine organisms. Both hal3 and suvanine inhibited the ATPase, RNA binding, and serine protease activities of NS3 helicase with IC50 values of 8, 8, and 14 µM, and 7, 3, and 34 µM, respectively. However, the dengue virus (DENV) NS3 helicase, which shares a catalytic core (consisting mainly of ATPase and RNA binding sites) with HCV NS3 helicase, was not inhibited by hal3 and suvanine, even at concentrations of 100 µM. Therefore, we conclude that hal3 and suvanine specifically inhibit HCV NS3 helicase via an interaction with an allosteric site in NS3 rather than binding to the catalytic core. This led to the inhibition of all NS3 activities, presumably by inducing conformational changes. |
| first_indexed | 2024-12-10T08:05:42Z |
| format | Article |
| id | doaj.art-938becb12fd0415aa67046233a4f8b5f |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-12-10T08:05:42Z |
| publishDate | 2014-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-938becb12fd0415aa67046233a4f8b5f2022-12-22T01:56:41ZengMDPI AGMarine Drugs1660-33972014-01-0112146247610.3390/md12010462md12010462Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine SpongeAtsushi Furuta0Kazi Abdus Salam1Idam Hermawan2Nobuyoshi Akimitsu3Junichi Tanaka4Hidenori Tani5Atsuya Yamashita6Kohji Moriishi7Masamichi Nakakoshi8Masayoshi Tsubuki9Poh Wee Peng10Youichi Suzuki11Naoki Yamamoto12Yuji Sekiguchi13Satoshi Tsuneda14Naohiro Noda15Department of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, JapanRadioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, JapanDepartment of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, JapanRadioisotope Center, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, JapanDepartment of Chemistry, Biology and Marine Science, University of the Ryukyus, Nishihara, Okinawa 903-0213, JapanResearch Institute for Environmental Management Technology, National Institute of Advanced Industrial Science and Technology (AIST), 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, JapanDepartment of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, JapanDepartment of Microbiology, Division of Medicine, Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo-shi, Yamanashi 409-3898, JapanInstitute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, JapanInstitute of Medical Chemistry, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, JapanDepartment of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #15-02, Level 15, Singapore 117599, SingaporeDepartment of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #15-02, Level 15, Singapore 117599, SingaporeDepartment of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #15-02, Level 15, Singapore 117599, SingaporeBiomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, JapanDepartment of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, JapanDepartment of Life Science and Medical Bioscience, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, JapanHepatitis C virus (HCV) is an important etiological agent that is responsible for the development of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV nonstructural protein 3 (NS3) helicase is a possible target for novel drug development due to its essential role in viral replication. In this study, we identified halisulfate 3 (hal3) and suvanine as novel NS3 helicase inhibitors, with IC50 values of 4 and 3 µM, respectively, from a marine sponge by screening extracts of marine organisms. Both hal3 and suvanine inhibited the ATPase, RNA binding, and serine protease activities of NS3 helicase with IC50 values of 8, 8, and 14 µM, and 7, 3, and 34 µM, respectively. However, the dengue virus (DENV) NS3 helicase, which shares a catalytic core (consisting mainly of ATPase and RNA binding sites) with HCV NS3 helicase, was not inhibited by hal3 and suvanine, even at concentrations of 100 µM. Therefore, we conclude that hal3 and suvanine specifically inhibit HCV NS3 helicase via an interaction with an allosteric site in NS3 rather than binding to the catalytic core. This led to the inhibition of all NS3 activities, presumably by inducing conformational changes.http://www.mdpi.com/1660-3397/12/1/462marine organismhalisulfate 3suvaninehepatitis C virusNS3 helicasedengue virus |
| spellingShingle | Atsushi Furuta Kazi Abdus Salam Idam Hermawan Nobuyoshi Akimitsu Junichi Tanaka Hidenori Tani Atsuya Yamashita Kohji Moriishi Masamichi Nakakoshi Masayoshi Tsubuki Poh Wee Peng Youichi Suzuki Naoki Yamamoto Yuji Sekiguchi Satoshi Tsuneda Naohiro Noda Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge Marine Drugs marine organism halisulfate 3 suvanine hepatitis C virus NS3 helicase dengue virus |
| title | Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge |
| title_full | Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge |
| title_fullStr | Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge |
| title_full_unstemmed | Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge |
| title_short | Identification and Biochemical Characterization of Halisulfate 3 and Suvanine as Novel Inhibitors of Hepatitis C Virus NS3 Helicase from a Marine Sponge |
| title_sort | identification and biochemical characterization of halisulfate 3 and suvanine as novel inhibitors of hepatitis c virus ns3 helicase from a marine sponge |
| topic | marine organism halisulfate 3 suvanine hepatitis C virus NS3 helicase dengue virus |
| url | http://www.mdpi.com/1660-3397/12/1/462 |
| work_keys_str_mv | AT atsushifuruta identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT kaziabdussalam identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT idamhermawan identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT nobuyoshiakimitsu identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT junichitanaka identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT hidenoritani identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT atsuyayamashita identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT kohjimoriishi identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT masamichinakakoshi identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT masayoshitsubuki identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT pohweepeng identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT youichisuzuki identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT naokiyamamoto identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT yujisekiguchi identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT satoshitsuneda identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge AT naohironoda identificationandbiochemicalcharacterizationofhalisulfate3andsuvanineasnovelinhibitorsofhepatitiscvirusns3helicasefromamarinesponge |