Abstract Title
Targeting calicivirus entry – a VP2 peptide inhibitor of Feline Calicivirus
Presenter
Charlotte Lewis, University of Glasgow Centre for Virus Research
Co-Author(s)
Charlotte Lewis*, Lee Sherry*, Millie Freitag*, Hagar Sasvari*, David Bhella*
*Institute: University of Glasgow Centre for Virus Research, School of Infection and Immunity, University of Glasgow, UK
Abstract Category
Prevention & Control (antivirals)
Abstract
Feline Calicivirus (FCV) is a respiratory pathogen that causes mild to severe respiratory symptoms, gingivostomatitis, and fever in cats. Virulent systemic (VS) strains of FCV have emerged, which are associated with multi-organ failure, extensive mucosal ulceration, and oedema, leading to high morbidity and mortality rates. Current vaccines are not fully efficacious against VS-FCV strains, and there are currently no approved direct-acting antivirals. Therefore, there is a significant need for novel therapeutics that effectively target both VS and non-VS strains.
FCV entry into the host cell is facilitated, upon receptor engagement, by the assembly of a portal-like structure consisting of twelve copies of the minor capsid protein VP2. Viral genomic RNA (gRNA) is released through this structure into the host cell cytoplasm. Six of the twelve copies of VP2 bind electrostatically to the major capsid protein VP1. A short peptide was designed to occlude these contact sites on VP1, to prevent complete assembly of the VP2 portal structure. Incubation with low micromolar concentrations of peptide considerably reduces the infectivity of six FCV isolates, including three virulent systemic strains. A cryo-electron microscopy (cryo-EM) structure of the acute respiratory FCV strain 273 complexed with peptide suggests that this peptide occupies the VP2 binding site on VP1, disrupting VP2-VP1 interactions and ultimately preventing viral gRNA release. Therefore, inhibition of VP2 portal assembly may be an effective antiviral mechanism against virulent systemic strains of FCV.
FCV entry into the host cell is facilitated, upon receptor engagement, by the assembly of a portal-like structure consisting of twelve copies of the minor capsid protein VP2. Viral genomic RNA (gRNA) is released through this structure into the host cell cytoplasm. Six of the twelve copies of VP2 bind electrostatically to the major capsid protein VP1. A short peptide was designed to occlude these contact sites on VP1, to prevent complete assembly of the VP2 portal structure. Incubation with low micromolar concentrations of peptide considerably reduces the infectivity of six FCV isolates, including three virulent systemic strains. A cryo-electron microscopy (cryo-EM) structure of the acute respiratory FCV strain 273 complexed with peptide suggests that this peptide occupies the VP2 binding site on VP1, disrupting VP2-VP1 interactions and ultimately preventing viral gRNA release. Therefore, inhibition of VP2 portal assembly may be an effective antiviral mechanism against virulent systemic strains of FCV.