Discovery of Multitarget Agents Active as Broad-Spectrum Antivirals and Correctors of Cystic Fibrosis Transmembrane Conductance Regulator for Associated Pulmonary Diseases

Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations,...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-02, Vol.60 (4), p.1400-1416
Main Authors: Tassini, Sabrina, Sun, Liang, Lanko, Kristina, Crespan, Emmanuele, Langron, Emily, Falchi, Federico, Kissova, Miroslava, Armijos-Rivera, Jorge I, Delang, Leen, Mirabelli, Carmen, Neyts, Johan, Pieroni, Marco, Cavalli, Andrea, Costantino, Gabriele, Maga, Giovanni, Vergani, Paola, Leyssen, Pieter, Radi, Marco
Format: Article
Language:English
Subjects:
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cystic Fibrosis - drug therapy
Cystic Fibrosis - genetics
Cystic Fibrosis - virology
Cystic Fibrosis Transmembrane Conductance Regulator - chemistry
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Drug Discovery
Enterovirus - drug effects
Enterovirus Infections - drug therapy
Enterovirus Infections - genetics
Enterovirus Infections - virology
Humans
Models, Molecular
Molecular Docking Simulation
Mutation
Protein Folding - drug effects
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
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Summary:Enteroviruses (EVs) are among the most frequent infectious agents in humans worldwide and represent the leading cause of upper respiratory tract infections. No drugs for the treatment of EV infections are currently available. Recent studies have also linked EV infection with pulmonary exacerbations, especially in cystic fibrosis (CF) patients, and the importance of this link is probably underestimated. The aim of this work was to develop a new class of multitarget agents active both as broad-spectrum antivirals and as correctors of the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding defect responsible for >90% of CF cases. We report herein the discovery of the first small molecules able to simultaneously act as correctors of the F508del-CFTR folding defect and as broad-spectrum antivirals against a panel of EVs representative of all major species.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01521