A conserved glutathione binding site in poliovirus is a target for antivirals and vaccine stabilisation

DOI: 10.1038/s42003-022-04252-5

Authors: Mohammad W. Bahar (University of Oxford) , Veronica Nasta (University of Oxford; University of Florence) , Helen Fox (The National Institute for Biological Standards and Control) , Lee Sherry (University of Leeds) , Keith Grehan (University of Leeds) , Claudine Porta (University of Oxford; The Pirbright Institute) , Andrew J. Macadam (The National Institute for Biological Standards and Control) , Nicola J. Stonehouse (University of Leeds) , David J. Rowlands (University of Leeds) , Elizabeth E. Fry (University of Oxford) , David I. Stuart (University of Oxford; Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Communications Biology , VOL 5

State: Published (Approved)
Published: November 2022
Diamond Proposal Number(s): 20223

Abstract: Strategies to prevent the recurrence of poliovirus (PV) after eradication may utilise non-infectious, recombinant virus-like particle (VLP) vaccines. Despite clear advantages over inactivated or attenuated virus vaccines, instability of VLPs can compromise their immunogenicity. Glutathione (GSH), an important cellular reducing agent, is a crucial co-factor for the morphogenesis of enteroviruses, including PV. We report cryo-EM structures of GSH bound to PV serotype 3 VLPs showing that it can enhance particle stability. GSH binds the positively charged pocket at the interprotomer interface shown recently to bind GSH in enterovirus F3 and putative antiviral benzene sulphonamide compounds in other enteroviruses. We show, using high-resolution cryo-EM, the binding of a benzene sulphonamide compound with a PV serotype 2 VLP, consistent with antiviral activity through over-stabilizing the interprotomer pocket, preventing the capsid rearrangements necessary for viral infection. Collectively, these results suggest GSH or an analogous tight-binding antiviral offers the potential for stabilizing VLP vaccines.

Diamond Keywords: Poliomyelitis; Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios IV-Titan Krios IV at Diamond

Added On: 28/11/2022 10:46

Discipline Tags:

Vaccines Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)