Discovery of BPR2-D2 compound in inhibiting Chikungunya viral RNA synthesis by replicon systems

 Highlights

• BPR2-D2, a coumarin derivative, is able to inhibit Chikungunya virus (CHIKV) RNA replication with a high selective index.

• BPR2-D2 can inhibit replication of Sindbis virus, which is an arthritogenic alphavirus as CHIKV

• The CHIKV replicon systems, which can be surrogates for studying CHIKV RNA replication, are applicable and convenient for antiviral screening.

ABSTRACT

Chikungunya virus (CHIKV), an alphavirus in the Togaviridae family, is transmitted to humans through mosquito bites and can lead to severe complications in newborns and elders. Its RNA genome functions as mRNA to produce viral nonstructural proteins, which assemble into replication complex for synthesizing new viral genomic and subgenomic RNA within the cytoplasm. Previous studies have established a CHIKV replicon system, that can express CHIKV replication complex from viral genomic RNA and an eGFP reporter from subgenomic RNA, to study viral RNA replication and screen antivirals against the CHIKV RNA replication. Additionally, researchers have discovered that BPR2-D2, which is classified to furanocoumarin, exhibits potential as a broad-spectrum antiviral drug. In this research, we applied the replicon system to evaluate the antiviral activity of BPR2-D2 against CHIKV RNA replication. The effective concentration was 10.47 ± 0.02297 nM for inhibiting 50% of CHIKV genomic RNA replication with high selective index. Moreover, we validated the antiviral effect of BPR2-D2 with the authentic infection of Sindbis virus, which is also an arthritogenic alphavirus. The molecular docking analysis was applied to suggest possible targets of BPR2-D2 among CHIKV nonstructural proteins. Taken together, this research demonstrated that BPR2-D2 can be a promising antiviral against CHIKV.

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https://www.sciencedirect.com/science/article/pii/S2319417026000053