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.

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-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.

journal_name

ChemMedChem

journal_title

ChemMedChem

authors

Lillsunde KE,Tomašič T,Schult P,Lohmann V,Kikelj D,Tammela P

doi

10.1002/cmdc.201800724

subject

Has Abstract

pub_date

2019-02-05 00:00:00

pages

334-342

issue

3

eissn

1860-7179

issn

1860-7187

journal_volume

14

pub_type

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