Inhibition of early RNA replication in Chikungunya and Dengue virus by lycorine: In vitro and in silico studies

Arboviruses such as chikungunya virus (CHIKV) and dengue virus (DENV) collectively afflict millions of individuals worldwide particularly in endemic countries like India, leading to substantial morbidity and mortality. With the lack of effective vaccines for both CHIKV and DENV in India, the search...

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Published in:	Biochemical and biophysical research communications Vol. 730; p. 150393
Main Authors:	Agrawal, Tanvi, Siddqui, Gazala, Dahiya, Ridhima, Patidar, Aanchal, Madan, Upasna, Das, Supratik, Asthana, Shailendra, Samal, Sweety, Awasthi, Amit
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 20-10-2024
Subjects:	Amaryllidaceae Alkaloids - chemistry Amaryllidaceae Alkaloids - pharmacology Animals Antiviral Antiviral Agents - chemistry Antiviral Agents - pharmacology Cell Line Chikungunya Chikungunya virus - drug effects Chikungunya virus - genetics Chlorocebus aethiops Computer Simulation Dengue Dengue Virus - drug effects Dengue Virus - genetics Humans Lycorine Molecular Docking Simulation Natural product Phenanthridines - chemistry Phenanthridines - pharmacology RNA dependent RNA polymerase RNA Replication - drug effects RNA, Viral - genetics RNA, Viral - metabolism Chikungunya Natural product Antiviral Lycorine Dengue RNA dependent RNA polymerase
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Summary:	Arboviruses such as chikungunya virus (CHIKV) and dengue virus (DENV) collectively afflict millions of individuals worldwide particularly in endemic countries like India, leading to substantial morbidity and mortality. With the lack of effective vaccines for both CHIKV and DENV in India, the search for antiviral compounds becomes paramount to control these viral infections. In line with this, our investigation was focused on screening natural compounds for their potential antiviral activity against CHIKV and DENV. Using different assays, including plaque assay, immunofluorescence, and reverse transcription-quantitative real-time PCR (qRT-PCR), out of 109 natural compounds tested, we confirmed lycorine's in vitro antiviral activity against CHIKV and DENV at low micromolar concentrations in different cell types. Time of addition assays indicated that lycorine does not impede viral entry. Additionally, qRT-PCR results along with time of addition assay suggested that lycorine interferes with the synthesis of negative strand viral RNA. Molecular docking analysis was done to understand the mode of inhibition of viral replication. The results revealed that the most likely binding site with the highest binding affinity of lycorine, was at the palm and finger domains, in the vicinity of the catalytic site of CHIKV and DENV RNA-dependent RNA polymerase (RdRp). Collectively, our data underscores the potential of lycorine to be developed as a direct acting inhibitor for DENV and CHIKV, addressing the critical need of requirement of an antiviral in regions where these viruses pose significant public health threats. •Arboviruses like CHIKV & DENV affect millions yearly, notably in India.•Lack of approved vaccine for CHIKV and DENV in India underscores urgency for antiviral compounds.•Lycorine identified as potent inhibitor against both CHIKV & DENV.•In vitro assays confirm lycorine's efficacy at low micromolar concentrations.•In silico analysis suggests that lycorine targets the catalytic site of viral RNA dependent RNA polymerase.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-291X 1090-2104 1090-2104
DOI:	10.1016/j.bbrc.2024.150393