beta-Carboline derivatives as novel antivirals for herpes simplex virus.
Gonzalez, M. M., Cabrerizo, F. M., Baiker, A., Erra-Balsells, R., Osterman, A., Nitschko, H. and Vizoso-Pinto, M. G.
Max von Pettenkofer-Institut, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU, D-80336 Munich, Germany; IIB-INTECH-CONICET, Universidad Nacional de San Martin, 7130 Chascomus, Buenos Aires, Argentina. Electronic address: mgonzalez@intech.gov.ar.
IIB-INTECH-CONICET, Universidad Nacional de San Martin, 7130 Chascomus, Buenos Aires, Argentina.
Bavarian Health and Food Safety Authority, Oberschleissheim, Germany.
CONICET, Universidad de Buenos Aires, Centro de Investigacion en Hidratos de Carbono (CIHIDECAR), Facultad de Ciencias Exactas y Naturales, Pabellon II, 3er P., Ciudad Universitaria, 1428 Buenos Aires, Argentina.
Max von Pettenkofer-Institut, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU, D-80336 Munich, Germany; German Center for Infection Research (DZIF), partner site Munich, Germany.
Max von Pettenkofer-Institut, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU, D-80336 Munich, Germany; INSIBIO-CONICET, Departamento Biomedico, Facultad de Medicina, Universidad Nacional de Tucuman, 4000 San Miguel de Tucuman, Argentina. Electronic address: mgvizoso@fm.unt.edu.ar.
Several commercial and novel synthetic beta-carbolines (betaCs) were evaluated for their antiviral activity against herpes simplex virus type 1 (HSV-1) using an adapted MTS assay. Of 21 drugs tested, although 11 exerted antiviral activity at non-cytotoxic concentrations, only 3 of them [9-methyl-norharmane (9-Me-nHo), 9-methyl-harmane (9-Me-Ho) and 6-methoxy-harmane (6-MeO-Ho)] completely avoided virus-driven cytopathic effects. Half-maximal effective concentrations (EC50 values) (4.9 +/- 0.4, 5.9 +/- 0.8 and 19.5 +/- 0.3microM, respectively) and selectivity indexes (88.8, 40.2 and 7.0, respectively) of the latter three betaCs against HSV-1 were determined by MTS, flow cytometry and plaque reduction assays. The mode of action of these drugs was also evaluated. According to time-of-addition assays, the selected compounds were not virucidal and did not interfere with attachment or penetration of HSV-1, but interfered with later events of virus infection. Western blot studies showed that early and late protein expression was significantly delayed or even suppressed. Herpes simplex virus type 2 (HSV-2) was also inhibited by the selected substances in a similar manner. Interestingly, 6-MeO-Ho, 9-Me-Ho and 9-Me-nHo restricted HSV-1 ICP0 localisation to the nucleus during later stages of infection, possibly affecting its functionality in the cytoplasm where ICP0 normally inhibits antiviral signalling and promotes viral replication. In silico prediction of ADME (Absorption, Distribution, Metabolism and Excretion) properties showed that all compounds fulfilled Lipinski's rule and their calculated absorptions were >95%.
International Journal of Antimicrobial Agents 52(4): 459-468 (2018)