In vitro antiviral activity of beta-carbolines against RNA viruses.

PICCINI, L.E.; PANOZZO ZENERE J,D.; DAMONTE, E.B.; PONCE, M.A.; CASTILLA, V.

Congreso; 26th International Conference on Antiviral Research; 2013

The beta-carboline skeleton is present in many natural and synthetic products associated with biological activities. The natural harmol, harmine, harmane, norharmane and their synthetic 9-methyl derivatives were evaluated for their antiviral activity in vitro against enveloped viruses with RNA genome: two human pathogens, the hemorrhagic fever viruses dengue type 2 (DENV-2) and Junin virus (JUNV), and vesicular stomatitis virus (VSV), which has veterinary importance. First, Vero cells were incubated with different concentrations of the compounds and after 48 h of treatment cell viability was determined by the MTS method and the 50% cytotoxic concentration (CC50) was determined. Harmine was the most cytotoxic compound suggesting that the C-7 methoxy group adversely affect cell viability. All N-methylated derivatives display higher CC50 values than natural compounds indicating that methylation of the pyrrole ring caused a marked reduction in the cytotoxicity. The antiviral activity was determined by a virus yield inhibition assay. To this end, cells infected with VSV, DENV or JUNV were treated with non-cytotoxic concentrations of each compound for 48 h and virus yields were quantified by plaque assay. The 50% effective concentration (EC50) was determined and the selectivity index (SI) was calculated as the ratio CC50/EC50. Harmane and N-methyl-harmane were active against VSV with SI values of 16 and 30.6, respectively. Harmol and N-methyl-harmine were active against DENV-2 with SI values of 56.2 and 61.2, whereas N-methylnorharmane was the most active compound against JUNV (SI=15). The active compounds also achieved a clear reduction in viral antigen expression detected by indirect immunofluorescence assays. Compounds did not show direct inactivating activity, with the exception of N-methyl-harmine which exhibited a weak virucidal effect against DENV-2. Therefore, natural and synthetic beta-carbolines are able to inhibit the replication of different RNA viruses, being DENV-2 the most susceptible to the action of this kind of compounds.