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.

Retracted Article: The synthesis and biological activity of marine alkaloid derivatives and analogues

“…Previous studies have shown that HCV replication could be inhibited by targeting the host cell protein Hsp90. Preliminary work Lillsunde et al 218 found that compounds with a pyrrolamide and 4,5,6,7-tetrahydrobenzo[1,2-d] thiazole structure could inhibit the replication of HCV type 1b. It was found that compounds containing the unsubstituted 2-amino group had the most effective biological activity in terms of drug SAR.…”

Anti-influenza virus activity of benzo[d]thiazoles that target heat shock protein 90

“…We have previously reported that 4,5,6,7-tetrahydrobenzo[d]thiazoles that were originally designed as DNA gyrase B inhibitors can suppress hepatitis C virus replication, which appears to involve their binding to Hsp90 [50,51]. Two other well-known DNA gyrase B inhibitors, novobiocin and coumermycin A1, also show inhibitory activities against Hsp90 and virus replication [52][53][54].…”

“…The microscale thermophoresis assay has been previously reported [50,51]. The well-known Hsp90 inhibitor 17-DMAG was included as the positive control.…”

The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2

“…SARS-CoV-2 has shown greater similarity with other viruses with regard to a need for host HSP90 protein, a non-conventional class purine utilizing enzyme, as a chaperone for viral proteins, helping prevent proteasomal degradation. Targeting HSP90 could inhibit replication of Kaposi sarcoma-associated herpesvirus (KHSV) (100) hepatitis C virus (HCV) (101) and also the human coronaviruses MERS-CoV and SARS-CoV (102). In a similar manner, ex vivo experiments involving transcriptomic profiling of SARS-CoV-2 infected human cell lines have shown that HSP90 inhibition impaired viral replication and activation of proinflammatory genes in primary human airway epithelial cells (103).…”