info:eu-repo/semantics/article
β-Carboline derivatives as novel antivirals for herpes simplex virus
Fecha
2018-10Registro en:
Gonzalez, Maria Micaela; Cabrerizo, Franco Martín; Baiker, Armin; Erra Balsells, Rosa; Osterman, Andreas; et al.; β-Carboline derivatives as novel antivirals for herpes simplex virus; Elsevier Science; International Journal of Antimicrobial Agents; 52; 4; 10-2018; 459-468
0924-8579
CONICET Digital
CONICET
Autor
Gonzalez, Maria Micaela
Cabrerizo, Franco Martín
Baiker, Armin
Erra Balsells, Rosa
Osterman, Andreas
Nitschko, Hans
Vizoso Pinto, María Guadalupe
Resumen
Several commercial and novel synthetic β-carbolines (βCs) 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 (EC 50 values) (4.9 ± 0.4, 5.9 ± 0.8 and 19.5 ± 0.3 µM, respectively) and selectivity indexes (88.8, 40.2 and 7.0, respectively) of the latter three βCs 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%.