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
2018
Authors: Lillsunde KE, Tomašič T, Schult P, Lohmann V, Kikelj D, Tammela P
CellNetworks People: Lohmann Volker
Journal: ChemMedChem. 2018 Dec 13. doi: 10.1002/cmdc.201800724

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 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2-amine structure show inhibition of HCV replication and potential 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 compounds 2, 5 and 8. 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.