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4. Helicases as Antiviral Drug Targets   Funds : Research Fund for the Control of Infectious Diseases (investigator-initiated projects) Project Status : Closed Reference No. : 01030182 Project Title : Helicases as Antiviral Drug Targets Applicant(s) : Huang JD(1) Zheng BJ(2) Sun H(3) Affiliation(s) : Department of Biochemistry, The University of Hong Kong(1) Department of Microbiology, The University of Hong Kong(2) Department of Chemistry, The University of Hong Kong(3) Approved Amount (HK$) : $805,000.00 Abstract : BACKGROUND Helicases is required for proteins to access, read or rearrange genetic information. To identify novel inhibitors of SCV, we developed an in vitro helicase assay, and screened many potential anti-viral drugs already in clinic use for their inhibitory effects on SCV helicase activities. Using this biochemical approach, we identified bismuth containing compounds as potent inhibitors of SCV helicase activity in vitro, and SCV replication in cell cultures. OBJECTIVE To provide a foundation for antiviral drug development, we will expand our screen to identify more helicase inhibitors against SCV. We will also validate SCV helicase as drug target.DESIGN AND METHODS Purified SCV helicase proteins will be used to probe whether the putative helicase inhibitors, RBC (a bismuth compound) can directly bind to the SCV helicase. Furthermore, we will generate bismuth-resistant SCV strains to validate that helicase is indeed the target. Helicase inhibitors against the herpes simplex virus (HSV) have recently been shown to effectively control HSV infection in animal models. We will test known helicase inhibitors of HSV and the hepatitis C virus (HCV) for their effect on SCV helicase activities. Promising compounds will be further tested in cell cultures for their effect on SCV replication. EXPECTED RESULTS Inhibitory effect of bismuth compounds can either interfering directly with SCV helicase or inhibit other viral and host processes. If bismuth binds directly to SCV helicase, and SCV helicase mutants resistant to a bismuth compound can be selected, it is a strong indication that SCV helicase is the drug target. By expanding our screen, we shall provide more lead compounds for drug design and development.SIGNIFICANCE Since the compounds studied in this work are currently either in clinical use or in clinical trial, potentially they can be quickly adapted to treat SARS. Furthermore, they may be used as antiviral drugs against other viruses.s Keywords : SARS, Helicase, Infectious diseases, bismuth, virus, antiviral drug, HSV, HCV, coronavirus, metal binding domain Instruments : Remarks : Dissemination Report : [PDF file] 01030182dr.pdf Final Report : [PDF file] 01030182fr.pdf [add to bookmark]

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