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

• Published in: Journal of medicinal chemistry Vol. 60; no. 4; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.02.2017; Amer Chemical Soc
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Chemistry, Medicinal; 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; Life Sciences & Biomedicine; Models, Molecular; Molecular Docking Simulation; Mutation; Pharmacology & Pharmacy; Protein Folding - drug effects; Science & Technology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; PHOSPHATIDYLINOSITOL 4-KINASES; 4-KINASE III-BETA; IN-VITRO; DC-SIGN; DRUG DISCOVERY; ENTEROVIRUS 71; RESPIRATORY VIRAL-INFECTIONS; INHIBITORS; DELTA-F508-CFTR CORRECTORS; CELL REGULATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01521

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.