New acridone-4-carboxylic acid derivatives as potential inhibitors of Hepatitis C virus infection

Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4

“…According to our results, Fac4 presented the ability to partially intercalate in 184 dsRNA, however it does not inhibit T7 RNA polymerase. As reported before (Stankiewicz-185 Drogon et al, 2010;Stankiewicz-Drogon et al, 2008), it is presumed that HCV replication 186 cannot be inhibited by dsRNA intercalation alone, and probably it is due to a combined effect 187 between different modes of action. Therefore, replication inhibition by Fac4 may be somewhat 188 related to dsRNA intercalation, which is a replication intermediate.…”

“…This 170 could be explained by the way acridones usually act against virus infection. Some authors argue 171 that their nucleic acid intercalation ability and interaction with viral enzymes are the main 172 mechanisms by which these compounds act (Adams, 2002;Stankiewicz-Drogon et al, 2010;workers (Stankiewicz-Drogon et al, 2010;Stankiewicz-Drogon et al, 2008) reinforces this 175 assumption. Acridones showed inhibition of NS3 helicase, T7 RNA polymerase (topology and 176 function similar to HCV NS5B) and strong double-stranded RNA intercalation property.…”

“…Some acridones from Rutaceae plants showed great 153 antiviral activity against viruses with DNA genomes like herpes simplex virus serotypes 1 and 2 154 (HSV-1 and HSV-2), human cytomegalovirus (HCMV) and Epstein-Barr virus (Chansriniyom et 155 al., 2009;Itoigawa et al, 2003;Takemura et al, 1995;Yamamoto et al, 1989). For RNA 156 viruses, acridones presented activity against HIV-1, bovine viral diarrhea virus (BVDV), all 157 serotypes of dengue virus (DENV) and HCV, the last three belonging to the Flaviviridae family 158 (Fujiwara et al, 1999;Houe, 2003;Mazzucco et al, 2015;Raney et al, 2010;Sepulveda et al, 159 2008;Stankiewicz-Drogon et al, 2010;Stankiewicz-Drogon et al, 2008;Tabarrini et al, 2006;160 Turpin et al, 1998). 161 Our results showed that Fac4 inhibited up to 92% of HCV replication in the context of either the 162 subgenomic replicon or full length JFH1 HCVcc.…”

“…Therefore, replication inhibition by Fac4 may be somewhat 188 related to dsRNA intercalation, which is a replication intermediate. However it is likely that 189 other mode of action, such as enzymatic inhibition is also involved (Stankiewicz-Drogon et al, 190 2010;Stankiewicz-Drogon et al, 2008;Tabarrini et al, 2006). Another possible explanation for 191 the antiviral activity of Fac4 is the targeting of cellular components.…”

“…For that, T7 RNA 122 polymerase was used, which as stated earlier, is similar to NS5B viral polymerase (Stankiewicz-123 Drogon et al, 2010;Stankiewicz-Drogon et al, 2008). Fac4 did not present any activity on T7 124 enzymatic process since no difference was observed when compared to the control (Fig.…”