title: In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses.
abstract: BACKGROUND
  Rhinovirus infections do not only cause common colds, but may also trigger severe exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Even though rhinoviruses have been the focus of extensive drug development efforts in the past, an anti-rhinoviral drug still has to make it to the market. In the past, the viral capsid protein VP1 has been shown to be an important target for the development of antiviral molecules. Furthermore, many different chemical scaffolds appear to possess the properties that are required to inhibit virus replication by this mechanism of action. I-6602, an analogue of the rhinovirus inhibitor pirodavir, was previously identified as a potent inhibitor of rhinovirus infection. Here, we describe the antiviral activity of its analogue ca603, a molecule with a modified linker structure, and corroborate its mechanism of action as a capsid binder.
  
  
  RESULTS
  The molecule ca603 shows antiviral activity against a panel of rhino-and enteroviruses. Cross-resistance is observed against viruses with mutations that render them resistant to the inhibitory effect of the capsid binder pleconaril and thermostability assays demonstrate that the compound binds and stabilizes the viral capsid. Binding of the molecule to the VP1 protein is corroborated by in silico modeling.
  
  
  CONCLUSIONS
  It is confirmed that ca603 inhibits rhinovirus replication by interaction with the VP1 protein and, by this, allows to further expand the chemical diversity of capsid-binding molecules.
authors.affiliation: Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, B-3000, Leuven, Belgium. lacroixceline@gmail.com.
authors.forename: Céline
authors.initials: C
authors.lastname: Lacroix
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, I-09124, Cagliari, Italy. lsamuela@tiscali.it.
authors.forename: Samuela
authors.initials: S
authors.lastname: Laconi
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, I-09124, Cagliari, Italy. fangius@unica.it.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Angius
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185, Rome, Italy. antonio.coluccia@uniroma1.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185, Rome, Italy. romano.silvestri@uniroma1.it.
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, I-09124, Cagliari, Italy. pompei@unica.it.
authors.forename: Raffaello
authors.initials: R
authors.lastname: Pompei
authors.affiliation: Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, B-3000, Leuven, Belgium. johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, B-3000, Leuven, Belgium. pieter.leyssen@rega.kuleuven.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D010069:Oxadiazoles / Q000494:pharmacology*; D010080:Oxazoles; D010880:Piperidines / Q000494:pharmacology*; D011485:Protein Binding; D011724:Pyridazines / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D010069:Oxadiazoles; D010080:Oxazoles; D010880:Piperidines; D011724:Pyridazines; C115201:pleconaril; C074589:pirodavir