β-Carboline derivatives as novel antivirals for herpes simplex virus

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-norharman...

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Autores principales:	Gonzalez, M.M., Cabrerizo, F.M., Baiker, A., Erra-Balsells, R., Osterman, A., Nitschko, H., Vizoso-Pinto, M.G.
Formato:	JOUR
Materias:	Alkaloids Antiherpetic Antiviral Carbolines Herpes simplex virus ICP0 1 ethyl norharmane 6 bromo harmine 6 chloro harmane 6 chloro harmine 6 chloro norharmane 6 methoxy harmane 6,8 dibromo harmane 6,8 dibromo harmine 6,8 dibromo norharmane 6,8 dichloro harmane 6,8 dichloro harmine 8 bromo harmane 8 bromo norharmane 8 chloro harmane 8 chloro norharmane 9 methyl harmane 9 methyl norharmane antivirus agent beta carboline beta carboline derivative harmaline harman harmine unclassified drug animal cell antiviral activity Article assay controlled study cytotoxicity drug absorption drug distribution drug excretion drug metabolism drug selectivity EC50 flow cytometry Herpes simplex virus 2 Human alphaherpesvirus 1 MTS assay nonhuman plaque reduction assay priority journal protein expression time of addition assay virus attachment virus replication Western blotting
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_09248579_v52_n4_p459_Gonzalez
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_09248579_v52_n4_p459_Gonzalez
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spelling	todo:paper_09248579_v52_n4_p459_Gonzalez2023-10-03T15:46:06Z β-Carboline derivatives as novel antivirals for herpes simplex virus Gonzalez, M.M. Cabrerizo, F.M. Baiker, A. Erra-Balsells, R. Osterman, A. Nitschko, H. Vizoso-Pinto, M.G. Alkaloids Antiherpetic Antiviral Carbolines Herpes simplex virus ICP0 1 ethyl norharmane 6 bromo harmine 6 chloro harmane 6 chloro harmine 6 chloro norharmane 6 methoxy harmane 6,8 dibromo harmane 6,8 dibromo harmine 6,8 dibromo norharmane 6,8 dichloro harmane 6,8 dichloro harmine 8 bromo harmane 8 bromo norharmane 8 chloro harmane 8 chloro norharmane 9 methyl harmane 9 methyl norharmane antivirus agent beta carboline beta carboline derivative harmaline harman harmine unclassified drug animal cell antiviral activity Article assay controlled study cytotoxicity drug absorption drug distribution drug excretion drug metabolism drug selectivity EC50 flow cytometry Herpes simplex virus 2 Human alphaherpesvirus 1 MTS assay nonhuman plaque reduction assay priority journal protein expression time of addition assay virus attachment virus replication Western blotting 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%. © 2018 JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_09248579_v52_n4_p459_Gonzalez
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Alkaloids Antiherpetic Antiviral Carbolines Herpes simplex virus ICP0 1 ethyl norharmane 6 bromo harmine 6 chloro harmane 6 chloro harmine 6 chloro norharmane 6 methoxy harmane 6,8 dibromo harmane 6,8 dibromo harmine 6,8 dibromo norharmane 6,8 dichloro harmane 6,8 dichloro harmine 8 bromo harmane 8 bromo norharmane 8 chloro harmane 8 chloro norharmane 9 methyl harmane 9 methyl norharmane antivirus agent beta carboline beta carboline derivative harmaline harman harmine unclassified drug animal cell antiviral activity Article assay controlled study cytotoxicity drug absorption drug distribution drug excretion drug metabolism drug selectivity EC50 flow cytometry Herpes simplex virus 2 Human alphaherpesvirus 1 MTS assay nonhuman plaque reduction assay priority journal protein expression time of addition assay virus attachment virus replication Western blotting
spellingShingle	Alkaloids Antiherpetic Antiviral Carbolines Herpes simplex virus ICP0 1 ethyl norharmane 6 bromo harmine 6 chloro harmane 6 chloro harmine 6 chloro norharmane 6 methoxy harmane 6,8 dibromo harmane 6,8 dibromo harmine 6,8 dibromo norharmane 6,8 dichloro harmane 6,8 dichloro harmine 8 bromo harmane 8 bromo norharmane 8 chloro harmane 8 chloro norharmane 9 methyl harmane 9 methyl norharmane antivirus agent beta carboline beta carboline derivative harmaline harman harmine unclassified drug animal cell antiviral activity Article assay controlled study cytotoxicity drug absorption drug distribution drug excretion drug metabolism drug selectivity EC50 flow cytometry Herpes simplex virus 2 Human alphaherpesvirus 1 MTS assay nonhuman plaque reduction assay priority journal protein expression time of addition assay virus attachment virus replication Western blotting Gonzalez, M.M. Cabrerizo, F.M. Baiker, A. Erra-Balsells, R. Osterman, A. Nitschko, H. Vizoso-Pinto, M.G. β-Carboline derivatives as novel antivirals for herpes simplex virus
topic_facet	Alkaloids Antiherpetic Antiviral Carbolines Herpes simplex virus ICP0 1 ethyl norharmane 6 bromo harmine 6 chloro harmane 6 chloro harmine 6 chloro norharmane 6 methoxy harmane 6,8 dibromo harmane 6,8 dibromo harmine 6,8 dibromo norharmane 6,8 dichloro harmane 6,8 dichloro harmine 8 bromo harmane 8 bromo norharmane 8 chloro harmane 8 chloro norharmane 9 methyl harmane 9 methyl norharmane antivirus agent beta carboline beta carboline derivative harmaline harman harmine unclassified drug animal cell antiviral activity Article assay controlled study cytotoxicity drug absorption drug distribution drug excretion drug metabolism drug selectivity EC50 flow cytometry Herpes simplex virus 2 Human alphaherpesvirus 1 MTS assay nonhuman plaque reduction assay priority journal protein expression time of addition assay virus attachment virus replication Western blotting
description	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%. © 2018
format	JOUR
author	Gonzalez, M.M. Cabrerizo, F.M. Baiker, A. Erra-Balsells, R. Osterman, A. Nitschko, H. Vizoso-Pinto, M.G.
author_facet	Gonzalez, M.M. Cabrerizo, F.M. Baiker, A. Erra-Balsells, R. Osterman, A. Nitschko, H. Vizoso-Pinto, M.G.
author_sort	Gonzalez, M.M.
title	β-Carboline derivatives as novel antivirals for herpes simplex virus
title_short	β-Carboline derivatives as novel antivirals for herpes simplex virus
title_full	β-Carboline derivatives as novel antivirals for herpes simplex virus
title_fullStr	β-Carboline derivatives as novel antivirals for herpes simplex virus
title_full_unstemmed	β-Carboline derivatives as novel antivirals for herpes simplex virus
title_sort	β-carboline derivatives as novel antivirals for herpes simplex virus
url	http://hdl.handle.net/20.500.12110/paper_09248579_v52_n4_p459_Gonzalez
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β-Carboline derivatives as novel antivirals for herpes simplex virus

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