VP1 crystal structure-guided exploration and optimization of 4,5-dimethoxybenzene-based inhibitors of rhinovirus 14 infection

Laurène Da Costa; Manon Roche; Els Scheers; Antonio Coluccia; Johan Neyts; Thierry Terme; Pieter Leyssen; Romano Silvestri; Patrice Vanelle

doi:10.1016/j.ejmech.2016.03.049

VP1 crystal structure-guided exploration and optimization of 4,5-dimethoxybenzene-based inhibitors of rhinovirus 14 infection

Eur J Med Chem. 2016 Jun 10:115:453-62. doi: 10.1016/j.ejmech.2016.03.049. Epub 2016 Mar 19.

Authors

Laurène Da Costa¹, Manon Roche¹, Els Scheers², Antonio Coluccia³, Johan Neyts⁴, Thierry Terme¹, Pieter Leyssen², Romano Silvestri⁵, Patrice Vanelle⁶

Affiliations

¹ Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, Marseille, France.
² KU Leuven-University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium.
³ Institut Pasteur Italy, Department of Drug Chemistry and Technologies, Sapienza University, I-00185 Rome, Italy.
⁴ 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.
⁵ Institut Pasteur Italy, Department of Drug Chemistry and Technologies, Sapienza University, I-00185 Rome, Italy. Electronic address: romano.silvestri@uniroma1.it.
⁶ Aix-Marseille Université, Institut de Chimie Radicalaire, UMR 7273 CNRS, 27 Boulevard Jean Moulin, Marseille, France. Electronic address: patrice.vanelle@univ-amu.fr.

PMID: 27049678
DOI: 10.1016/j.ejmech.2016.03.049

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).

Keywords: Capsid inhibitors; HRV14; In silico design; TDAE; VP1 protein.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry*
Antiviral Agents / pharmacology*
Benzene Derivatives / chemistry*
Benzene Derivatives / pharmacology*
HeLa Cells
Humans
Models, Molecular
Rhinovirus / chemistry*

Substances

Antiviral Agents
Benzene Derivatives