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

Katja-Emilia M Lillsunde, Tihomir Tomašič, Philipp Schult, Volker Lohmann, Danijel Kikelj, Päivi Tammela

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

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 mu m.

Originalspråkengelska
TidskriftChemMedChem : chemistry enabling drug discovery.
Volym14
Utgåva3
Sidor (från-till)334-342
Antal sidor9
ISSN1860-7179
DOI
StatusPublicerad - 5 feb 2019
MoE-publikationstypA1 Tidskriftsartikel-refererad

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