Identification of Drug Repurposing Candidates for Coxsackievirus B3 Infection in iPSC-Derived Brain-like Endothelial...

Area of Science:

• Virology
• Neuroscience
• Pharmacology

Background:

• Coxsackievirus B3 (CVB3) causes severe diseases like meningitis and myocarditis.
• Current treatments for CVB3 are limited to supportive care, lacking targeted antiviral therapies or vaccines.
• Understanding CVB3's impact on the blood-brain barrier (BBB) is crucial for developing new treatments.

Purpose of the Study:

• To investigate the transcriptomic alterations induced by CVB3 infection in human brain endothelial cells (iBECs).
• To identify potential drug repurposing candidates for treating CVB3 infections, particularly those affecting the BBB.
• To elucidate CVB3-associated pathways within the BBB.

Main Methods:

• Reanalysis of a published RNA sequencing dataset from CVB3-infected iBECs.
• Integration of Gene Set Enrichment Analysis (GSEA), EnrichR, and iLINCs-based perturbagen analysis.
• Systems-level analysis of host transcriptomic response at 2- and 5-day post-infection.

Main Results:

• CVB3 infection induced dynamic changes in host gene expression.
• Downregulated pathways included ribosomal biogenesis and protein synthesis.
• Upregulated pathways involved defense responses to viruses and interferon production.
• iLINCs analysis identified MEK, PDGFR, and VEGF inhibitors as potential antivirals.
• Pelitinib and neratinib were highlighted as candidates to disrupt CVB3 pathology at the BBB.

Conclusions:

• The study provides insights into CVB3-induced pathways in iBECs.
• Potential drug repurposing candidates, including pelitinib and neratinib, were identified for CVB3 treatment.
• Targeting CVB3 pathology at the BBB presents a promising therapeutic strategy.