beta-CARBOLINE DERIVATIVES AS NOVEL ANTIVIRALS FOR HERPES SIMPLEX VIRUSES

GONZALEZ, M.M.; CABRERIZO, F.M.; BAIKER, A.; ERRA-BALSELLS, R.; OSTERMAN, A.; NITSCHKO, H.; VIZOSO PINTO, M. G.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018

0924-8579

Several commercial and novel synthetic βCs were evaluated for their antiviral activity against HSV-1 using an adapted MTS assay. Of 21 drugs tested, although 11 exerted antiviral activity at non-cytotoxic concentrations, only three of them (9-methyl-norharmane, 9-methyl-harmane and 6-methoxy-harmane) completely avoided virus-driven cytopathic effects. Effective concentrations (EC50, 4.9 ± 0.4 μM, 5.9 ± 0.8 μM and 19.5 ± 0.3 μM, respectively) and selectivity indexes (SI, 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 with later events of virus infection. Western blot studies showed that early and late protein expression was significantly delayed or even suppressed. HSV-2 was also inhibited by the selected substances in a similar way. Interestingly, 6- methoxy-harmane, 9-methyl-harmane and 9-methyl-norharmane restricted HSV- 1 ICP0 localization to the nucleus during later stages of infection, possibly affecting its functionality at the cytoplasm, where ICP0 normally inhibits antiviral signaling 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 over 95%.