Transcriptome-Driven Repurposing for Chikungunya Virus: A Connectivity Map Approach

Introduction: Chikungunya virus (CHIKV) causes recurrent outbreaks worldwide with no approved antiviral therapy available. Drug repurposing offers a rapid and cost-effective alternative to de novo drug development. This study aimed to identify existing approved drugs that can reverse or mimic a protective gene expression signature induced by immunomodulatory compounds in CHIKV-infected cells.

Methods: A gene expression profile was derived from CHIKV-infected cells treated with cAIMP (a STING agonist) or scleroglucan (a Dectin‑1 agonist), dataset GeoNCBI GSE197744. The resulting significant gene signature was uploaded to the Connectivity Map platform (www.clue.io). Drugs with a high connectivity score (TAS > 0.8 and TAG > 0) were selected as candidates for repurposing.

Results: The analysis yielded five drugs with transcriptional signatures matching the input profile: everolimus (mTOR inhibitor), afatinib (EGFR/HER2 inhibitor), ponatinib (multi‑kinase inhibitor), PHA‑848125 (dual CDK/tropomyosin receptor kinase inhibitor), and brefeldin‑A (protein transport inhibitor). These compounds are predicted to induce a cellular state like that produced by cAIMP/scleroglucan in infected cells.

Conclusions: The four identified drugs represent mechanistically diverse candidates that could potentially suppress CHIKV replication or modulate host immunity. Further in vitro and in vivo validation is required to confirm their antiviral efficacy. However, this computational approach demonstrates a rapid and unbiased strategy for repurposing approved drugs for emerging viral diseases, such as Chikungunya.