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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

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 a...

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Bibliographic Details
Main Authors: Lillsunde, Katja-Emilia (Author) , Schult, Philipp (Author) , Lohmann, Volker (Author)
Format: Article (Journal)
Language:English
Published: 2019
In: ChemMedChem
Year: 2018, Volume: 14, Issue: 3, Pages: 334-342
ISSN:1860-7187
DOI:10.1002/cmdc.201800724
Online Access:Verlag, Volltext: https://doi.org/10.1002/cmdc.201800724
Verlag, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201800724
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Author Notes:Katja-Emilia Lillsunde, Tihomir Tomašič, Philipp Schult, Volker Lohmann, Danijel Kikelj, and Päivi Tammela
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Summary: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-tetrahydrobenzo[1,2-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.
Item Description:First published: 13 December 2018
Gesehen am 16.08.2019
Physical Description:Online Resource
ISSN:1860-7187
DOI:10.1002/cmdc.201800724

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