β-Carboline derivatives as novel antivirals for herpes simplex virus

Autor: Armin Baiker, M. Micaela Gonzalez, Andreas Osterman, Rosa Erra-Balsells, Franco M. Cabrerizo, Hans Nitschko, Maria Guadalupe Vizoso-Pinto
Rok vydání: 2018
Předmět:
0301 basic medicine
Herpesvirus 2
Human
viruses
Herpesvirus 1
Human
Virus Replication
medicine.disease_cause
01 natural sciences
purl.org/becyt/ford/1 [https]
Chlorocebus aethiops
Pharmacology (medical)
ADME
Molecular Structure
medicine.diagnostic_test
Chemistry
Ciencias Químicas
General Medicine
Viral Load
Antiherpetic
Infectious Diseases
CIENCIAS NATURALES Y EXACTAS
Microbiology (medical)
Cell Survival
Antiviral Agents
Virus
Flow cytometry
Ciencias Biológicas
Late protein
Structure-Activity Relationship
03 medical and health sciences
Alkaloids
Western blot
purl.org/becyt/ford/1.4 [https]
medicine
Animals
Humans
Antiviral
Vero Cells
EC50
Dose-Response Relationship
Drug
010405 organic chemistry
Otras Ciencias Químicas
Molecular biology
Herpes Simplex Virus
0104 chemical sciences
Química Orgánica
030104 developmental biology
Herpes simplex virus
Viral replication
DNA
Viral
Icp0
Virología
Carbolines
Zdroj: CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
ISSN: 0924-8579
DOI: 10.1016/j.ijantimicag.2018.06.019
Popis: 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%. Fil: Gonzalez, Maria Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina. Ludwig Maximilians Universitat; Alemania Fil: Cabrerizo, Franco Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Baiker, Armin. Bavarian Health and Food Safety Authority; Alemania Fil: Erra Balsells, Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones en Hidratos de Carbono. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones en Hidratos de Carbono; Argentina Fil: Osterman, Andreas. Ludwig Maximilians Universitat; Alemania. German Center for Infection Research; Alemania Fil: Nitschko, Hans. Ludwig Maximilians Universitat; Alemania. German Center for Infection Research; Alemania Fil: Vizoso Pinto, María Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Medicina. Departamento Biomédico; Argentina. Ludwig Maximilians Universitat; Alemania
Databáze: OpenAIRE
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