Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole Derivatives |
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Authors: | Katja-Emilia Lillsunde Dr Tihomir Tomašič Dr Philipp Schult Dr Volker Lohmann Prof Danijel Kikelj Dr Päivi Tammela |
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Affiliation: | 1. Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland;2. Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia;3. Department of Infectious Diseases, Molecular Virology, University of Heidelberg, Heidelberg, Germany |
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Abstract: | Cellular chaperones that belong to the heat-shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5,6,7-tetrahydrobenzo1,2-d]thiazole-2-amine structure show inhibition of HCV replication and binding to Hsp90, a series of twelve novel compounds based on this scaffold was designed and synthesized. The aim was improved Hsp90 affinity and anti-HCV activity. Through structural optimization, improved binding to Hsp90 and specific HCV inhibition in genotype 1b and 2a replicon models was achieved for three compounds belonging to the newly synthesized series. Furthermore, these compounds efficiently inhibited replication of full-length HCV genotype 2a in a reporter virus RNA assay with IC50 values ranging from 0.03 to 0.6 μm . |
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Keywords: | hepatitis C virus Hsp90 inhibitors replicon model |
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