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

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

  • Eur J Med Chem. 2015:96:318-29. doi: 10.1016/j.ejmech.2015.04.030.
Matias Rey-Carrizo 1,  Sabrina Gazzarrini 2,  Salomé Llabrés 3,  Marta Frigolé-Vivas 1,  Jordi Juárez-Jiménez 3,  Mercè Font-Bardia 4,  Lieve Naesens 5,  Anna Moroni 2,  F Javier Luque 3,  Santiago Vázquez 6
Affiliations

Affiliations

  • 1 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, E-08028, Spain.
  • 2 Department of Biosciences and National Research Council (CNR) Biophysics Institute (IBF), University of Milan, Via Celoria 26, 20133 Milan, Italy.
  • 3 Departament de Fisicoquímica, Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Prat de la Riba 171, Santa Coloma de Gramenet E-08921, Spain.
  • 4 Unitat de Difracció de RX, Centres Científics i Tecnològics (CCiTUB), Universitat de Barcelona, Solé i Sabarís 1-3, Barcelona E-08028, Spain.
  • 5 Rega Institute for Medical Research, KU Leuven, B-3000 Leuven, Belgium.
  • 6 Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona, E-08028, Spain. Electronic address: svazquez@ub.edu.
PMID: 25899336 DOI: 10.1016/j.ejmech.2015.04.030
Abstract

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.

Keywords

Amantadine; Influenza A; M2 channel; Molecular dynamics; Polycyclic amines; V27A mutant.

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