In silico identification, design and synthesis of novel piperazine-based antiviral agents targeting the hepatitis C virus helicase.
A structure-based virtual screening of commercial compounds was carried out on the HCV NS3 helicase structure, with the aim to identify novel inhibitors of HCV replication. Among a selection of 13 commercial structures, one compound was found to inhibit the subgenomic HCV replicon in the low micromolar range. Different series of new piperazine-based analogues were designed and synthesised, and among them, several novel structures exhibited antiviral activity in the HCV replicon assay. Some of the new compounds were also found to inhibit HCV NS3 helicase function in vitro, and one directly bound NS3 with a dissociation constant of 570 ± 270 nM.
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, King Edward VII Avenue, Cardiff CF103NB, UK. Electronic address: bassettom@cardiff.ac.uk.
Marcella
M
Bassetto
Rega Institute for Medical Research, University of Leuven, Belgium.
Pieter
P
Leyssen
Rega Institute for Medical Research, University of Leuven, Belgium.
Johan
J
Neyts
Department of Chemistry & Biochemistry, University of Wisconsin- Milwaukee, Milwaukee, WI 53211, United States.
Mark M
MM
Yerukhimovich
Department of Chemistry & Biochemistry, University of Wisconsin- Milwaukee, Milwaukee, WI 53211, United States.
David N
DN
Frick
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, King Edward VII Avenue, Cardiff CF103NB, UK.
Matthew
M
Courtney-Smith
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff, King Edward VII Avenue, Cardiff CF103NB, UK.
Andrea
A
Brancale
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D012093:Replicon / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D010879:Piperazines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
Anti-HCV activity; HCV NS3-helicase; NS3 helicase inhibitors; Piperazine derivatives; Structure-based virtual screening