In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses
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In vitro characterisation of a pleconaril/ pirodavir-like compound with potent activity against rhinoviruses Céline Lacroix1, Samuela Laconi2, Fabrizio Angius2, Antonio Coluccia3, Romano Silvestri3, Raffaello Pompei2, Johan Neyts1* and Pieter Leyssen1
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.
Body of text The genus Enterovirus comprises several human pathogens with a substantial clinical impact on society like poliovirus (PV), rhinoviruses (HRV) and enterovirus 71 (EV71) [1]. Rhinoviruses cause common colds in healthy people but may trigger exacerbations in patients with asthma and COPD [2, 3]. Vaccination against rhinovirus infection is not yet feasible due to the large number of serotypes. Treatment with small-molecule inhibitors therefore seems to be the best possible option to lower the burden of this disease. To date, the rhinoviral capsid and protease are the best characterized antiviral targets. However, a drug has still to be approved for clinical use [1]. In the past, several early-stage rhinovirus * Correspondence: [email protected] 1 Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, KU Leuven, Rega Institute for Medical Research, B‐3000 Leuven, Belgium Full list of author information is available at the end of the article
inhibitors, referred to as capsid binders, were discovered. Pleconaril, pirodavir and vapendavir are the most extensively studied capsid binders (Fig. 1). In 2002, the New Drug Application for pleconaril (Schering-Plough) as drug against the commo
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