title: The novel immunosuppressive protein kinase C inhibitor sotrastaurin has no pro-viral effects on the replication cycle of hepatitis B or C virus.
abstract: The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients.
authors: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors: Thomas
authors: T
authors: von Hahn
authors: Andreas
authors: A
authors: Schulze
authors: Ivan
authors: I
authors: Chicano Wust
authors: Benjamin
authors: B
authors: Heidrich
authors: Thomas
authors: T
authors: Becker
authors: Eike
authors: E
authors: Steinmann
authors: Fabian A
authors: FA
authors: Helfritz
authors: Katrin
authors: K
authors: Rohrmann
authors: Stephan
authors: S
authors: Urban
authors: Michael P
authors: MP
authors: Manns
authors: Thomas
authors: T
authors: Pietschmann
authors: Sandra
authors: S
authors: Ciesek
mesh_terms: D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D012367:RNA, Viral; C543528:sotrastaurin; D016572:Cyclosporine; D011493:Protein Kinase C; D019703:Calcineurin