Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.
Bioorg Med Chem
; 28(1): 115130, 2020 01 01.
Article
em En
| MEDLINE
| ID: mdl-31753804
ABSTRACT
The influenza virus hemagglutinin (HA) mediates membrane fusion after viral entry by endocytosis. The fusion process requires drastic low pH-induced HA refolding and is prevented by arbidol and tert-butylhydroquinone (TBHQ). We here report a class of superior inhibitors with indole-substituted spirothiazolidinone structure. The most active analogue 5f has an EC50 value against influenza A/H3N2 virus of 1â¯nM and selectivity index of almost 2000. Resistance data and in silico modeling indicate that 5f combines optimized fitting in the TBHQ/arbidol HA binding pocket with a capability for endosomal accumulation. Both criteria appear relevant to achieve superior inhibitors of HA-mediated fusion.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antivirais
/
Compostos de Espiro
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Glicoproteínas de Hemaglutininação de Vírus da Influenza
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Influenza Humana
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Vírus da Influenza A Subtipo H3N2
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Tiazolidinas
/
Indóis
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article