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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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 |
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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 |
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