RESUMO
The influenza A virus nonstructural protein 1 (NS1), which is crucial for viral replication and immune evasion, has been identified as a significant drug target with substantial potential to contribute to the fight against influenza. The emergence of drug-resistant influenza A virus strains highlights the urgent need for novel therapeutics. This study proposes a combined theoretical criterion for the virtual screening of molecular libraries to identify candidate NS1 inhibitors. By applying the criterion to the ZINC Natural Product database, followed by ligand-based virtual screening and molecular docking, we proposed the most promising candidate as a potential NS1 inhibitor. Subsequently, the selected natural compound was experimentally evaluated, revealing measurable virus replication inhibition activity in cell culture. This approach offers a promising avenue for developing novel anti-influenza agents targeting the NS1 protein.
Assuntos
Antivirais , Produtos Biológicos , Simulação de Acoplamento Molecular , Proteínas não Estruturais Virais , Replicação Viral , Antivirais/farmacologia , Antivirais/química , Humanos , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Vírus da Influenza A/efeitos dos fármacos , Animais , Células Madin Darby de Rim Canino , CãesRESUMO
Influenza A virus (IAV) matrix protein 2 (M2), an ion channel, is crucial for virus infection, and therefore, an important anti-influenza drug target. Adamantanes, also known as M2 channel blockers, are one of the two classes of Food and Drug Administration-approved anti-influenza drugs, although their use was discontinued due to prevalent drug resistance. Fast emergence of resistance to current anti-influenza drugs have raised an urgent need for developing new anti-influenza drugs against resistant forms of circulating viruses. Here we propose a simple theoretical criterion for fast virtual screening of molecular libraries for candidate anti-influenza ion channel inhibitors both for wild type and adamantane-resistant influenza A viruses. After in silico screening of drug space using the EIIP/AQVN filter and further filtering of drugs by ligand based virtual screening and molecular docking we propose the best candidate drugs as potential dual inhibitors of wild type and adamantane-resistant influenza A viruses. Finally, guanethidine, the best ranked drug selected from ligand-based virtual screening, was experimentally tested. The experimental results show measurable anti-influenza activity of guanethidine in cell culture.
Assuntos
Antivirais/isolamento & purificação , Biologia Computacional/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Proteínas da Matriz Viral/antagonistas & inibidores , Antivirais/química , Antivirais/farmacologia , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Proteínas da Matriz Viral/químicaRESUMO
BACKGROUND: Due to the limitations of current antiviral therapies because of drug resistance and the emergence of new circulating viral strains, novel effective antivirals are urgently needed. Results of the previous drug repurposing by virtual screening of DrugBank revealed the anticholinergic drug cycrimine as a possible inhibitor of the influenza virus infection. METHODS: In this study we examined the potential antiviral activity of cycrimine in vitro. RESULTS: The experimental results showed the anti-influenza activity of cycrimine against two different influenza A subtypes in cell culture. CONCLUSIONS: The findings of this study suggest cycrimine as a potential therapeutic agent for influenza.
Assuntos
Simulação por Computador , Reposicionamento de Medicamentos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , CãesRESUMO
The influenza virus represents a permanent global health threat because it circulates not only within but also between numerous host populations, thereby frequently causing unexpected outbreaks in animals and humans with a generally unpredictable course of disease and epidemiology. Conventional influenza therapy is directed against the viral neuraminidase protein, which promotes virus release from infected cells, and the viral ion channel M2, which facilitates viral uncoating. However, these drugs, albeit effective, have a major drawback: their targets are of a highly variable sequence. As a consequence, the virus can readily acquire resistance by mutating the drug targets. Indeed, most seasonal A/H1N1 viruses and the 2009 H1N1 virus are resistant to M2 inhibitors, and a significant proportion of the seasonal A/H1N1 viruses are resistant to the neuraminidase inhibitor oseltamivir. Development of new effective drugs for treatment of disease during the regular influenza seasons and the possible influenza pandemic represents an important goal. The results presented here point out natural products as a promising source of low toxic and widely accessible drug candidates for treatment of the influenza disease. Natural products combined with new therapeutic targets and drug repurposing techniques, which accelerate development of new drugs, serve as an important platform for development of new influenza therapeutics.