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Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation

Influenza virus infections represent a major public health issue by causing annual epidemics and occasional pandemics that affect thousands of people worldwide. Vaccination is the main prophylaxis to prevent these epidemics/pandemics, although the effectiveness of licensed vaccines is rather limited...

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Autores principales: Boff, Laurita, Schreiber, André, da Rocha Matos, Aline, Del Sarto, Juliana, Brunotte, Linda, Munkert, Jennifer, Melo Ottoni, Flaviano, Silva Ramos, Gabriela, Kreis, Wolfgang, Castro Braga, Fernão, José Alves, Ricardo, Maia de Pádua, Rodrigo, Maria Oliveira Simões, Cláudia, Ludwig, Stephan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587960/
https://www.ncbi.nlm.nih.gov/pubmed/33096707
http://dx.doi.org/10.3390/molecules25204853
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author Boff, Laurita
Schreiber, André
da Rocha Matos, Aline
Del Sarto, Juliana
Brunotte, Linda
Munkert, Jennifer
Melo Ottoni, Flaviano
Silva Ramos, Gabriela
Kreis, Wolfgang
Castro Braga, Fernão
José Alves, Ricardo
Maia de Pádua, Rodrigo
Maria Oliveira Simões, Cláudia
Ludwig, Stephan
author_facet Boff, Laurita
Schreiber, André
da Rocha Matos, Aline
Del Sarto, Juliana
Brunotte, Linda
Munkert, Jennifer
Melo Ottoni, Flaviano
Silva Ramos, Gabriela
Kreis, Wolfgang
Castro Braga, Fernão
José Alves, Ricardo
Maia de Pádua, Rodrigo
Maria Oliveira Simões, Cláudia
Ludwig, Stephan
author_sort Boff, Laurita
collection PubMed
description Influenza virus infections represent a major public health issue by causing annual epidemics and occasional pandemics that affect thousands of people worldwide. Vaccination is the main prophylaxis to prevent these epidemics/pandemics, although the effectiveness of licensed vaccines is rather limited due to the constant mutations of influenza virus antigenic characteristics. The available anti-influenza drugs are still restricted and there is an increasing viral resistance to these compounds, thus highlighting the need for research and development of new antiviral drugs. In this work, two semisynthetic derivatives of digitoxigenin, namely C10 (3β-((N-(2-hydroxyethyl)aminoacetyl)amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), showed anti-influenza A virus activity by affecting the expression of viral proteins at the early and late stages of replication cycle, and altering the transcription and synthesis of new viral proteins, thereby inhibiting the formation of new virions. Such antiviral action occurred due to the interference in the assembly of viral polymerase, resulting in an impaired polymerase activity and, therefore, reducing viral replication. Confirming the in vitro results, a clinically relevant ex vivo model of influenza virus infection of human tumor-free lung tissues corroborated the potential of these compounds, especially C10, to completely abrogate influenza A virus replication at the highest concentration tested (2.0 µM). Taken together, these promising results demonstrated that C10 and C11 can be considered as potential new anti-influenza drug candidates.
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spelling pubmed-75879602020-10-29 Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation Boff, Laurita Schreiber, André da Rocha Matos, Aline Del Sarto, Juliana Brunotte, Linda Munkert, Jennifer Melo Ottoni, Flaviano Silva Ramos, Gabriela Kreis, Wolfgang Castro Braga, Fernão José Alves, Ricardo Maia de Pádua, Rodrigo Maria Oliveira Simões, Cláudia Ludwig, Stephan Molecules Article Influenza virus infections represent a major public health issue by causing annual epidemics and occasional pandemics that affect thousands of people worldwide. Vaccination is the main prophylaxis to prevent these epidemics/pandemics, although the effectiveness of licensed vaccines is rather limited due to the constant mutations of influenza virus antigenic characteristics. The available anti-influenza drugs are still restricted and there is an increasing viral resistance to these compounds, thus highlighting the need for research and development of new antiviral drugs. In this work, two semisynthetic derivatives of digitoxigenin, namely C10 (3β-((N-(2-hydroxyethyl)aminoacetyl)amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), showed anti-influenza A virus activity by affecting the expression of viral proteins at the early and late stages of replication cycle, and altering the transcription and synthesis of new viral proteins, thereby inhibiting the formation of new virions. Such antiviral action occurred due to the interference in the assembly of viral polymerase, resulting in an impaired polymerase activity and, therefore, reducing viral replication. Confirming the in vitro results, a clinically relevant ex vivo model of influenza virus infection of human tumor-free lung tissues corroborated the potential of these compounds, especially C10, to completely abrogate influenza A virus replication at the highest concentration tested (2.0 µM). Taken together, these promising results demonstrated that C10 and C11 can be considered as potential new anti-influenza drug candidates. MDPI 2020-10-21 /pmc/articles/PMC7587960/ /pubmed/33096707 http://dx.doi.org/10.3390/molecules25204853 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Boff, Laurita
Schreiber, André
da Rocha Matos, Aline
Del Sarto, Juliana
Brunotte, Linda
Munkert, Jennifer
Melo Ottoni, Flaviano
Silva Ramos, Gabriela
Kreis, Wolfgang
Castro Braga, Fernão
José Alves, Ricardo
Maia de Pádua, Rodrigo
Maria Oliveira Simões, Cláudia
Ludwig, Stephan
Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation
title Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation
title_full Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation
title_fullStr Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation
title_full_unstemmed Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation
title_short Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation
title_sort semisynthetic cardenolides acting as antiviral inhibitors of influenza a virus replication by preventing polymerase complex formation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587960/
https://www.ncbi.nlm.nih.gov/pubmed/33096707
http://dx.doi.org/10.3390/molecules25204853
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