Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones
BIOORGANIC & MEDICINAL CHEMISTRY, cilt.28, sa.1, 2020 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 28 Sayı: 1
- Basım Tarihi: 2020
- Doi Numarası: 10.1016/j.bmc.2019.115130
- Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, Chimica, EMBASE, MEDLINE
- İstanbul Üniversitesi Adresli: Evet
Özet
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 1 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.