2. Academic Validation
  3. β-Carboline derivatives as novel antivirals for herpes simplex virus

β-Carboline derivatives as novel antivirals for herpes simplex virus

  • Int J Antimicrob Agents. 2018 Oct;52(4):459-468. doi: 10.1016/j.ijantimicag.2018.06.019.
M Micaela Gonzalez 1,  Franco M Cabrerizo 2,  Armin Baiker 3,  Rosa Erra-Balsells 4,  Andreas Osterman 5,  Hans Nitschko 5,  María G Vizoso-Pinto 6
Affiliations

Affiliations

  • 1 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 Martín, 7130 Chascomús, Buenos Aires, Argentina. Electronic address: [email protected].
  • 2 IIB-INTECH-CONICET, Universidad Nacional de San Martín, 7130 Chascomús, Buenos Aires, Argentina.
  • 3 Bavarian Health and Food Safety Authority, Oberschleissheim, Germany.
  • 4 CONICET, Universidad de Buenos Aires, Centro de Investigación en Hidratos de Carbono (CIHIDECAR), Facultad de Ciencias Exactas y Naturales, Pabellón II, 3er P., Ciudad Universitaria, 1428 Buenos Aires, Argentina.
  • 5 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.
  • 6 Max von Pettenkofer-Institut, Virology, National Reference Center for Retroviruses, Faculty of Medicine, LMU, D-80336 Munich, Germany; INSIBIO-CONICET, Departamento Biomédico, Facultad de Medicina, Universidad Nacional de Tucumán, 4000 San Miguel de Tucumán, Argentina. Electronic address: [email protected].
PMID: 30006037 DOI: 10.1016/j.ijantimicag.2018.06.019
Abstract

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 (EC50 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%.

Keywords

Alkaloids; Antiherpetic; Antiviral; Carbolines; Herpes simplex virus; ICP0.

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