Semisynthetic Cardenolides acting as antiviral inhibitors of Influenza A virus replication by preventing Polymerase complex formation

Institute of Virology (IVM). Centre for Molecular Biology of Inflammation (ZMBE). Westfaelische Wilhelms University (WWU), 48149 Münster, Germany / Universidade Federal de Santa Catarina. Departamento de Ciências Faramacêuticas. Laboratório de Virologia Aplicada. Florianópolis, SC, Brasil.
Institute of Virology (IVM). Centre for Molecular Biology of Inflammation (ZMBE). Westfaelische Wilhelms University (WWU), 48149 Münster, Germany.
Institute of Virology (IVM). Centre for Molecular Biology of Inflammation (ZMBE). Westfaelische Wilhelms University (WWU), 48149 Münster, Germany / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Vírus Respiratórios e do Sarampo. Rio de Janeiro, RJ, Brasil.
Institute of Virology (IVM). Centre for Molecular Biology of Inflammation (ZMBE). Westfaelische Wilhelms University (WWU), 48149 Münster, Germany / Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Ciências Farmacêuticas. Belo Horizonte, MG, Brasil.
Institute of Virology (IVM). Centre for Molecular Biology of Inflammation (ZMBE). Westfaelische Wilhelms University (WWU), 48149 Münster, Germany.
Pharmaceutical Biology, Department of Biology, Friedrich-Alexander-University, 91054 Erlangen-Nuremberg, Germany.
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Ciências Farmacêuticas. Belo Horizonte, MG, Brasil.
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Ciências Farmacêuticas. Belo Horizonte, MG, Brasil.
Pharmaceutical Biology, Department of Biology, Friedrich-Alexander-University, 91054 Erlangen-Nuremberg, Germany.
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Ciências Farmacêuticas. Belo Horizonte, MG, Brasil.
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Ciências Farmacêuticas. Belo Horizonte, MG, Brasil.
Universidade Federal de Minas Gerais. Faculdade de Farmácia. Departamento de Ciências Farmacêuticas. Belo Horizonte, MG, Brasil.
Universidade Federal de Santa Catarina. Departamento de Ciências Farmacêuticas. Laboratório de Virologia Aplicada. Florianópolis, SC, Brasil.
Institute of Virology (IVM). Centre for Molecular Biology of Inflammation (ZMBE). Westfaelische Wilhelms University (WWU), 48149 Münster, Germany.

Abstract

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.

Keywords in Portuguese

Cardenolides semisintéticos
Inibição da atividade de polimerase
Mecanismo de ação
Inibição da atividade de polimerase

Keywords

Semisynthetic cardenolides
Anti-influenza
Mechanism of action
Polymerase activity inhibition

Publisher

MDPI

Citation

BOFF, Laurita et al. Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation. Molecules, v. 25, p. 1-18, 2020.

DOI

10.3390/molecules25204853

ISSN

1420-3049

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/45447

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Open access

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