title: VP1 crystal structure-guided exploration and optimization of 4,5-dimethoxybenzene-based inhibitors of rhinovirus 14 infection.
abstract: Human rhinoviruses (HRV) are the predominant cause of common colds and flu-like illnesses, but are also responsible for virus-induced exacerbations of asthma and chronic obstructive pulmonary disease. However, to date, no drug has been approved yet for clinical use. In this study, we present the results of the structure-based lead optimization of a class of new small-molecule inhibitors that we previously reported to bind into the pocket beneath the canyon of the VP1 protein. A small series of analogues that we designed based on the available structure and interaction data were synthesized and evaluated for their potency to inhibit the replication of HRV serotype 14. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-(pyridin-4-yl)phenyl)ethanol (3v) was found to be a potent inhibitor exhibiting micromolar activity (EC50 = 3.4 ± 1.0 μM) with a toxicity for HeLa cells that was significantly lower than that of our previous hit (LPCRW_0005, CC50 = 104.0 ± 22.2 μM; 3v, CC50 > 263 μM).
authors.affiliation: Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, Marseille, France.
authors.forename: Laurène
authors.initials: L
authors.lastname: Da Costa
authors.affiliation: Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, Marseille, France.
authors.forename: Manon
authors.initials: M
authors.lastname: Roche
authors.affiliation: KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Scheers
authors.affiliation: Institut Pasteur Italy, Department of Drug Chemistry and Technologies, Sapienza University, I-00185 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.affiliation: KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium. Electronic address: johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, Marseille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Terme
authors.affiliation: KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.affiliation: Institut Pasteur Italy, Department of Drug Chemistry and Technologies, Sapienza University, I-00185 Rome, Italy. Electronic address: romano.silvestri@uniroma1.it.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, Marseille, France. Electronic address: patrice.vanelle@univ-amu.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D012229:Rhinovirus / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D001555:Benzene Derivatives
keywords: Capsid inhibitors; HRV14; In silico design; TDAE; VP1 protein