Cargando…

Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model

Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. C...

Descripción completa

Detalles Bibliográficos
Autores principales: Spunde, Karina, Vigante, Brigita, Dubova, Unda Nelda, Sipola, Anda, Timofejeva, Irena, Zajakina, Anna, Jansons, Juris, Plotniece, Aiva, Pajuste, Karlis, Sobolev, Arkadij, Muhamadejev, Ruslan, Jaudzems, Kristaps, Duburs, Gunars, Kozlovska, Tatjana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317397/
https://www.ncbi.nlm.nih.gov/pubmed/35890072
http://dx.doi.org/10.3390/ph15070773
_version_ 1784755045538988032
author Spunde, Karina
Vigante, Brigita
Dubova, Unda Nelda
Sipola, Anda
Timofejeva, Irena
Zajakina, Anna
Jansons, Juris
Plotniece, Aiva
Pajuste, Karlis
Sobolev, Arkadij
Muhamadejev, Ruslan
Jaudzems, Kristaps
Duburs, Gunars
Kozlovska, Tatjana
author_facet Spunde, Karina
Vigante, Brigita
Dubova, Unda Nelda
Sipola, Anda
Timofejeva, Irena
Zajakina, Anna
Jansons, Juris
Plotniece, Aiva
Pajuste, Karlis
Sobolev, Arkadij
Muhamadejev, Ruslan
Jaudzems, Kristaps
Duburs, Gunars
Kozlovska, Tatjana
author_sort Spunde, Karina
collection PubMed
description Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. Cytoplasmic expression of the HBV core (HBc) gene driven by the exogenously delivered recombinant alphavirus RNA replicon was used for high level production of the full-length HBc protein in mammalian cells. HBV capsid assembly was assessed by native agarose gel immunoblot analysis, electron microscopy and inhibition of virion secretion in HepG2.2.15 HBV producing cell line. Induced fit docking simulation was applied for modelling the structural relationships of the synthesized compounds and HBc. The most efficient were the HAP class compounds—dihydropyrimidine 5-carboxylic acid n-alkoxyalkyl esters, which induced the formation of incorrectly assembled capsid products and their accumulation within the cells. HBc product accumulation in the cells was not detected with the reference HAP compound Bay 41-4109, suggesting different modes of action. A significant antiviral effect and substantially reduced toxicity were revealed for two of the synthesized compounds. Two new HAP compounds revealed a significant antiviral effect and a favorable toxicity profile that allows these compounds to be considered promising leads and drug candidates for the treatment of HBV infection. The established alphavirus based HBc expression approach allows for the specific selection of capsid assembly modulators directly in the natural cell environment.
format Online
Article
Text
id pubmed-9317397
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93173972022-07-27 Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model Spunde, Karina Vigante, Brigita Dubova, Unda Nelda Sipola, Anda Timofejeva, Irena Zajakina, Anna Jansons, Juris Plotniece, Aiva Pajuste, Karlis Sobolev, Arkadij Muhamadejev, Ruslan Jaudzems, Kristaps Duburs, Gunars Kozlovska, Tatjana Pharmaceuticals (Basel) Article Capsid assembly modulators (CAMs) have emerged as a promising class of antiviral agents. We studied the effects of twenty-one newly designed and synthesized CAMs including heteroaryldihydropyrimidine compounds (HAPs), their analogs and standard compounds on hepatitis B virus (HBV) capsid assembly. Cytoplasmic expression of the HBV core (HBc) gene driven by the exogenously delivered recombinant alphavirus RNA replicon was used for high level production of the full-length HBc protein in mammalian cells. HBV capsid assembly was assessed by native agarose gel immunoblot analysis, electron microscopy and inhibition of virion secretion in HepG2.2.15 HBV producing cell line. Induced fit docking simulation was applied for modelling the structural relationships of the synthesized compounds and HBc. The most efficient were the HAP class compounds—dihydropyrimidine 5-carboxylic acid n-alkoxyalkyl esters, which induced the formation of incorrectly assembled capsid products and their accumulation within the cells. HBc product accumulation in the cells was not detected with the reference HAP compound Bay 41-4109, suggesting different modes of action. A significant antiviral effect and substantially reduced toxicity were revealed for two of the synthesized compounds. Two new HAP compounds revealed a significant antiviral effect and a favorable toxicity profile that allows these compounds to be considered promising leads and drug candidates for the treatment of HBV infection. The established alphavirus based HBc expression approach allows for the specific selection of capsid assembly modulators directly in the natural cell environment. MDPI 2022-06-22 /pmc/articles/PMC9317397/ /pubmed/35890072 http://dx.doi.org/10.3390/ph15070773 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Spunde, Karina
Vigante, Brigita
Dubova, Unda Nelda
Sipola, Anda
Timofejeva, Irena
Zajakina, Anna
Jansons, Juris
Plotniece, Aiva
Pajuste, Karlis
Sobolev, Arkadij
Muhamadejev, Ruslan
Jaudzems, Kristaps
Duburs, Gunars
Kozlovska, Tatjana
Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model
title Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model
title_full Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model
title_fullStr Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model
title_full_unstemmed Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model
title_short Design and Synthesis of Hepatitis B Virus (HBV) Capsid Assembly Modulators and Evaluation of Their Activity in Mammalian Cell Model
title_sort design and synthesis of hepatitis b virus (hbv) capsid assembly modulators and evaluation of their activity in mammalian cell model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317397/
https://www.ncbi.nlm.nih.gov/pubmed/35890072
http://dx.doi.org/10.3390/ph15070773
work_keys_str_mv AT spundekarina designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT vigantebrigita designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT dubovaundanelda designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT sipolaanda designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT timofejevairena designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT zajakinaanna designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT jansonsjuris designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT plotnieceaiva designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT pajustekarlis designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT sobolevarkadij designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT muhamadejevruslan designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT jaudzemskristaps designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT dubursgunars designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel
AT kozlovskatatjana designandsynthesisofhepatitisbvirushbvcapsidassemblymodulatorsandevaluationoftheiractivityinmammaliancellmodel