Cryo-EM structures of Banna virus in multiple states reveal stepwise detachment of viral spikes.

Banna virus (BAV) is the prototype Seadornavirus, a class of reoviruses for which there has been little structural study. Here, we report atomic cryo-EM structures of three states of BAV virions-surrounded by 120 spikes (full virions), 60 spikes (partial virions), or no spikes (cores). BAV cores are double-layered particles similar to the cores of other non-turreted reoviruses, except for an additional protein component in the outer capsid shell, VP10. VP10 was identified to be a cementing protein that plays a pivotal role in the assembly of BAV virions by directly interacting with VP2 (inner capsid), VP8 (outer capsid), and VP4 (spike). Viral spikes (VP4/VP9 heterohexamers) are situated on top of VP10 molecules in full or partial virions. Asymmetrical electrostatic interactions between VP10 monomers and VP4 trimers are disrupted by high pH treatment, which is thus a simple way to produce BAV cores. Low pH treatment of BAV virions removes only the flexible receptor binding protein VP9 and triggers significant conformational changes in the membrane penetration protein VP4. BAV virions adopt distinct spatial organization of their surface proteins compared with other well-studied reoviruses, suggesting that BAV may have a unique mechanism of penetration of cellular endomembranes.

A combinatorial approach of structure-based virtual screening and molecular dynamics simulation towards the discovery of a highly selective inhibitor for VP9 coat protein of Banna virus.

Structure based virtual screening of two libraries containing 27,628 numbers of antiviral compounds was used to discover a few of the potent inhibitor molecules against Banna virus (BAV). Cross-docking studies with many common interfering proteins provided five of the highly selective inhibitor for BAV. Analyses of the leading molecules with ADME-Tox filtering tool and atomistic molecular dynamics simulation studies finally discovered a benzoxazolone derivative as one of the most promising molecules towards the highly selective inhibition of BAV. The theoretical calculations are also supported by the experimental evidences where the interactions between the hit ligand and a model peptide sequence, mimicking the VP9 protein of BAV, were studied. Overall the development of a personalized therapeutic towards the highly selective inhibition of BAV is discussed herein for the first time in literature.