New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

• DOI: 10.1016/j.ejmech.2015.04.030
• Publication Date: 2015-04-16T03:01:01Z
• Authors: Matias Rey-Carrizo; Sabrina Gazzarrini; Salomé Llabrés; Marta Frigolé-Vivas; Jordi Juárez-Jiménez; Mercè Font-Bardia; Lieve Naesens; Anna Moroni; F. Javier Luque; Santiago Vázquez
• Keywords: Models, Molecular; 0301 basic medicine; Síntesi orgànica; Cell Survival; Organic chemistry; Organic synthesis; Influenza A; Microbial Sensitivity Tests; Molecular dynamics; Influenzavirus; Antiviral Agents; M2 channel; Viral Matrix Proteins; Structure-Activity Relationship; 03 medical and health sciences; Dogs; Amantadine; Influenza A; M2 channel; Molecular dynamics; Polycyclic amines; V27A mutant; Amantadine; Influenza A; M2 channel; Molecular dynamics; Polycyclic amines; V27A mutant; Amantadine; Influenza A; M2 channel; Molecular dynamics; Polycyclic amines; V27A mutant; Amantadine; Influenza viruses; Animals; Polycyclic Compounds; Medicaments antivírics; Cells, Cultured; Binding Sites; Dose-Response Relationship, Drug; Molecular Structure; Polycyclic amines; Virus; 3. Good health; Antiviral agents; Influenza A virus; Viruses; Mutation; V27A mutant; Química orgànica

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.0(2,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.