Many viruses belonging to the Flaviviridae family are transmitted by invertebrate vectors. Among those transmitted by mosquitos, there are many human pathogens of great medical importance, such as Japanese encephalitis virus, West Nile virus, dengue virus, Zika virus, or yellow fever virus. Millions of people contract mosquito-borne diseases each year, leading to thousands of deaths. Co-circulation of genetically similar flaviviruses in the same areas result in the generation of crossreactive antibodies, which is of serious concern for the development of effective vaccines and diagnostic tests. This review provides comprehensive insight into the potential use of virus-like particles as safe and effective antigens in both diagnostics tests, as well as in the development of vaccines against several mosquito-borne flaviviruses. State of the Art Vaccine Development against Mosquito-borne FlavivirusesMosquito-borne viruses belonging to the Flavivirus genus comprise a large group of species that are spread worldwide. Due to climate changes, mosquitoes have gradually colonized new territories, resulting in the spread of associated flaviviruses. Depending on their vector, flaviviruses are classified as those transmitted by mosquitoes of Culex spp. [e.g., Japanese encephalitis virus (JEV) and West Nile virus (WNV)] or Aedes spp. [e.g., dengue virus (DENV), Zika virus (ZIKV), or yellow fever virus (YFV)]. The co-circulation of flaviviruses in different parts of the world can pose a problem for diagnosis on account of their high genetic and structural similarity; it can also result in antibody-dependent enhancement of infection (ADE), as initially observed for heterotypic infection with DENV. ADE (described in detail in Boxes 1 and 2) is the augmentation of secondary flaviviral infection due to pre-existing, nonneutralizing antibodies. Consequently, the development of efficient vaccines and diagnostic tests remain top priorities.Vaccines approved for human use against YFV, JEV, and DENV are based on live-attenuated or inactivated viruses. Both types of vaccines have some limitations. For live-attenuated vaccines there is some risk of virus reversion to pathogenic state, while the latter may not be completely inactivated. Thus, it is not surprising that other vaccine platforms are currently under investigation; these include viral vectors encoding Flavivirus genes, synthetic peptides, protein nanoparticles, mRNA vaccines, subunit antigens, and virus-like particles (VLPs). VLPs, due to their past successes in vaccination, probably have the greatest potential. They are composed of recombinant viral proteins, organized almost identically to the native virions. Moreover, VLPs do not contain viral genetic material, which makes them noninfectious, therefore potentially they can be used as optimum antigens in vaccine development. VLPs are often spontaneously produced during Flavivirus infection [1], and they can be generated using different expression systems. VLP-based vaccines against different human viruses, including hepatitis ...

Tick-borne encephalitis virus (TBEV) is a causative agent of tick-borne encephalitis (TBE), one of the most important human infections involving the central nervous system. Although effective vaccines are available on the market, they are recommended only in endemic areas. Despite many attempts, there are still no specific antiviral therapies for TBEV treatment. Previously, we synthesized a series of uridine derivatives of 2-deoxy sugars and proved that some compounds show antiviral activity against viruses from the Flaviviridae and Orthomyxoviridae families targeting the late steps of the N-glycosylation process, affecting the maturation of viral proteins. In this study, we evaluated a series of uridine derivatives of 2-deoxy sugars for their antiviral properties against two strains of the tick-borne encephalitis virus; the highly virulent TBEV strain Hypr and the less virulent strain Neudoerfl. Four compounds (2, 4, 10, and 11) showed significant anti-TBEV activity with IC50 values ranging from 1.4 to 10.2 µM and low cytotoxicity. The obtained results indicate that glycosylation inhibitors, which may interact with glycosylated membrane TBEV E and prM proteins, might be promising candidates for future antiviral therapies against TBEV.

Tick-borne encephalitis virus (TBEV) transmitted by ticks is a pathogen of great medical importance. As still no effective antiviral treatment is available, in the present study, a series of uridine glycoconjugates containing amide or/and 1,2,3-triazole moiety in the linker structure was synthesized and evaluated for the antiviral activity against two strains of TBEV: a highly virulent Hypr strain and less virulent Neudoerfl strain, using standardized previously in vitro assays. Our data have shown that four compounds from the series (18–21) possess strong activity against both TBEV strains. The half maximal inhibitory concentration (IC50) values of compounds 18–21 were between 15.1 and 3.7 μM depending on the virus strain, which along with low cytotoxicity resulted in high values of the selectivity index (SI). The obtained results suggest that these compounds may be promising candidates for further development of new therapies against flaviviruses.

A novel series of uridine glycoconjugates, derivatives of 4-aminophenyl 1-thioglycosides, was designed and synthesized. All compounds were evaluated in vitro for their antiviral activity against hepatitis C virus (HCV) and classical swine fever virus (CSFV), two important human and animal viral pathogens for which new or improved therapeutic options are needed. The antiviral activity of all synthesized compounds was confirmed using pseudo-plaque reduction assays in which a significant arrest of CSFV and HCV growth was observed in the presence of these compounds. Two of the synthesized compounds, 9 and 12, displayed a significant inhibitory effect on HCV and CSFV propagation with IC50 values of 4.9 and 13.5 µM for HCV and 4.2 and 4 µM for CSFV, respectively, with low cytotoxicity. Using various infection and replication models, we have shown that both compounds were able to significantly reduce viral genome replication by up to 90% with IC50 values in the low micromolar range. A structure activity analysis of the synthesized compounds showed that the high antiviral activity was attributed to the hydrophobicity of glycoconjugates and the introduction of elements capable to coordinate metal ions into the spacer connecting the sugar and uridine moiety, which can be useful in the development of new antiviral compounds in the future.

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