Onvansertib and vilazodone inhibit SARS-CoV-2 replication via suppression of METTL3 RNA-m6A enzymatic activity

Ting Zhang; Zi-Ling Wang; Xi-Ya Li; Rong-Hua Luo; Lu-Xi Zhang; Hong-Yi Zheng; Si-Dong Xiong; Wen-Lan Yang; Yong-Tang Zheng

Ting Zhang, Zi-Ling Wang, Xi-Ya Li, Rong-Hua Luo, Lu-Xi Zhang, Hong-Yi Zheng, Si-Dong Xiong, Wen-Lan Yang, Yong-Tang Zheng

Antiviral Research, doi:10.1016/j.antiviral.2026.106376

The continuous emergence of new SARS-CoV-2 variants limits the effectiveness of current vaccines and monoclonal antibodies, highlighting the urgent need for complementary antiviral strategies. Targeting host proteins that are exploited by the virus represents a promising approach to achieve broad-spectrum inhibition. Given the recently established proviral role of METTL3-dependent RNA m 6 A modification in SARS-CoV-2 replication, we conducted a structure-based virtual screening to repurpose compounds with acceptable safety profiles. Subsequent biochemical validation identified onvansertib and vilazodone as direct METTL3 binders and potent inhibitors of its methyltransferase activity. Notably, both compounds effectively suppressed the replication of ancestral SARS-CoV-2 and Omicron BA.2 variant in vitro. Mechanistically, each compound potentially enhanced the innate antiviral response of the host and repressed the expression of viral entry-associated host factors during infection; this observation is consistent with the established proviral role of METTL3. In summary, these findings not only substantiate METTL3 as a viable antiviral target but also lay the foundation for further research on the therapeutic potential of onvansertib and vilazodone against COVID-19.

Onvansertib and vilazodone could enhance host innate immune response activation and suppress proviral host factor expression during SARS-CoV-2 infection Given that both onvansertib and vilazodone inhibit SARS-CoV-2 replication, we next assessed the impact of each compound on host cells using RNA-seq. In infected Caco-2 cells treated with either compound, we identified thousands of differentially expressed genes (DEGs) compared to DMSO controls (Supplementary Fig. 6B ). Onvansertib treatment resulted in more DEGs (3, 683 up; 4, 562 down) than vilazodone (1,361 up; 1,683 down). For comparison, reanalysis of a public RNA-seq data (GSE167075) revealed METTL3 depletion altered 3,845 genes during SARS-CoV-2 infection. Despite the difference in numbers, all three conditions exhibited a consistent bias towards decreasing gene expression (Supplementary Fig. 6B ), suggesting that the down-regulated genes may be crucial for viral infection. To pinpoint the most critical shared responses, we performed an overlay analysis. It identified 155 genes that were consistently up-regulated across all three conditions (Supplementary Fig. 6C ). Gene Ontology (GO) analysis indicated their involvement in diverse cellular processes, including cell division, immune response and apoptotic process (Supplementary Fig. 6D ). Additionally, Gene Set Enrichment Analysis (GSEA) revealed a significant up-regulation of the RIG-I-like receptor signaling pathway (Supplementary Fig. 6G ), confirming..

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