2. Academic Validation
  3. In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses

In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses

  • Virol J. 2015 Jul 14;12:106. doi: 10.1186/s12985-015-0330-4.
Céline Lacroix 1,  Samuela Laconi 2,  Fabrizio Angius 3,  Antonio Coluccia 4,  Romano Silvestri 5,  Raffaello Pompei 6,  Johan Neyts 7,  Pieter Leyssen 8
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, B-3000, Leuven, Belgium. lacroixceline@gmail.com.
  • 2 Department of Biomedical Sciences, University of Cagliari, I-09124, Cagliari, Italy. lsamuela@tiscali.it.
  • 3 Department of Biomedical Sciences, University of Cagliari, I-09124, Cagliari, Italy. fangius@unica.it.
  • 4 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.
  • 5 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.
  • 6 Department of Biomedical Sciences, University of Cagliari, I-09124, Cagliari, Italy. pompei@unica.it.
  • 7 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.
  • 8 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.
PMID: 26169596 DOI: 10.1186/s12985-015-0330-4
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.

Findings: 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.

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