Effect of immature tick-borne encephalitis virus particles on antiviral activity of 5-aminoisoxazole-3-carboxylic acid adamantylmethyl esters

Abstract

Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is common in Europe and Asia and causes a severe disease of the central nervous system. A promising approach in the development of therapy for TBEV infection is the search for small molecule antivirals targeting the flavivirus envelope protein E, particularly its β-n-octyl-d-glucoside binding pocket (β-OG pocket). However, experimental studies of candidate antivirals may be complicated by varying amounts and different forms of the protein E in the virus samples. Viral particles with different conformations and arrangements of the protein E are produced during the replication cycle of flaviviruses, including mature, partially mature, and immature forms, as well as subviral particles lacking genomic RNA. The immature forms are known to be abundant in the viral population. We obtained immature virion preparations of TBEV, characterized them by RT-qPCR, and assessed in vivo and in vitro infectivity of the residual mature virions in the immature virus samples. Analysis of the β-OG pocket structure on the immature virions confirmed the possibility of binding of adamantylmethyl esters of 5-aminoisoxazole-3-carboxylic acid in the pocket. We demonstrated that the antiviral activity of these compounds in plaque reduction assay is significantly reduced in the presence of immature TBEV particles.

Structural diversity of tick-borne encephalitis virus particles in the inactivated vaccine based on strain Sofjin

“…Sample also contained a minute fraction of distorted particles, which were visually different from the normal particles. These distorted particles correspond to damaged, immature, and half-mature virions [ 25 , 26 ] ( Figure 1 ). By manually examining the dataset, we concluded that only 2% of the observed particles could be treated as distorted.…”