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Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases.

ABSTRACT: Several neurotropic viruses are members of the flavivirus and alphavirus families. Infections caused by these viruses may cause long-term neurological sequelae in humans. The continuous emergence of infections caused by viruses around the world, such as the chikungunya virus (CHIKV) (Alphavirus genus), the zika virus (ZIKV) and the yellow fever virus (YFV) (both of the Flavivirus genus), warrants the development of new strategies to combat them. Our study demonstrates the inhibitory potential of the water-soluble vitamin riboflavin against NS2B/NS3^pro of ZIKV and YFV and nsP2^pro of CHIKV. Riboflavin presents a competitive inhibition mode with IC₅₀ values in the medium µM range of 79.4 ± 5.0 µM for ZIKV NS2B/NS3^pro and 45.7 ± 2.9 μM for YFV NS2B/NS3^pro. Against CHIKV nsP2^pro, the vitamin showed a very strong effect (93 ± 5.7 nM). The determined dissociation constants (K_D) are significantly below the threshold value of 30 µM. The ligand binding increases the thermal stability between 4 °C and 8 °C. Unexpectedly, riboflavin showed inhibiting activity against another viral protein; the molecule was also able to inhibit the viral entry of CHIKV. Molecular dynamics simulations indicated great stability of riboflavin in the protease active site, which validates the repurposing of riboflavin as a promising molecule in drug development against the viruses presented here.

SUBMITTER: Eberle RJ

PROVIDER: S-EPMC9315535 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases.

Eberle Raphael J RJ Olivier Danilo S DS Amaral Marcos S MS Pacca Carolina C CC Nogueira Mauricio L ML Arni Raghuvir K RK Willbold Dieter D Coronado Monika A MA

Microorganisms 20220630 7

Several neurotropic viruses are members of the flavivirus and alphavirus families. Infections caused by these viruses may cause long-term neurological sequelae in humans. The continuous emergence of infections caused by viruses around the world, such as the chikungunya virus (CHIKV) (Alphavirus genus), the zika virus (ZIKV) and the yellow fever virus (YFV) (both of the Flavivirus genus), warrants the development of new strategies to combat them. Our study demonstrates the inhibitory potential of ...[more]

PMID: 35889050

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Project description:The impact of the host microbiota on arbovirus infections is currently not well understood. Arboviruses are viruses transmitted through the bites of infected arthropods, predominantly mosquitoes or ticks. The first site of arbovirus inoculation is the biting site in the host skin, which is colonized by a complex microbial community that could possibly influence arbovirus infection. We demonstrated that preincubation of arboviruses with certain components of the bacterial cell wall, including lipopolysaccharides (LPS) of some Gram-negative bacteria and lipoteichoic acids or peptidoglycan of certain Gram-positive bacteria, significantly reduced arbovirus infectivity in vitro. This inhibitory effect was observed for arboviruses of different virus families, including chikungunya virus of the Alphavirus genus and Zika virus of the Flavivirus genus, showing that this is a broad phenomenon. A modest inhibitory effect was observed following incubation with a panel of heat-inactivated bacteria, including bacteria residing on the skin. No viral inhibition was observed after preincubation of cells with LPS. Furthermore, a virucidal effect of LPS on viral particles was noticed by electron microscopy. Therefore, the main inhibitory mechanism seems to be due to a direct effect on the virus particles. Together, these results suggest that bacteria are able to decrease the infectivity of alphaviruses and flaviviruses. IMPORTANCE During the past decades, the world has experienced a vast increase in epidemics of alphavirus and flavivirus infections. These viruses can cause severe diseases, such as hemorrhagic fever, encephalitis, and arthritis. Several alpha- and flaviviruses, such as chikungunya virus, Zika virus, and dengue virus, are significant global health threats because of their high disease burden, their widespread (re-)emergence, and the lack of (good) anti-arboviral strategies. Despite the clear health burden, alphavirus and flavivirus infection and disease are not fully understood. A knowledge gap in the interplay between the host and the arbovirus is the potential interaction with host skin bacteria. Therefore, we studied the effect of (skin) bacteria and bacterial cell wall components on alphavirus and flavivirus infectivity in cell culture. Our results show that certain bacterial cell wall components markedly reduced viral infectivity by interacting directly with the virus particle.

Dataset Information

Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases.

Publications

Riboflavin, a Potent Neuroprotective Vitamin: Focus on Flavivirus and Alphavirus Proteases.

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