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

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

  • Antiviral Res. 2026 Apr:248:106376. doi: 10.1016/j.antiviral.2026.106376.
Ting Zhang 1,  Zi-Ling Wang 2,  Xi-Ya Li 3,  Rong-Hua Luo 1,  Lu-Xi Zhang 4,  Hong-Yi Zheng 1,  Si-Dong Xiong 5,  Wen-Lan Yang 6,  Yong-Tang Zheng 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
  • 2 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China; School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China.
  • 3 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China; KIZ-SU Joint Laboratory of Animal Model and Drug Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
  • 5 KIZ-SU Joint Laboratory of Animal Model and Drug Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
  • 6 Inner Mongolia Key Laboratory for Molecular Regulation of the Cell, College of Life Sciences, Inner Mongolia University, Hohhot, 010021, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China; School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China; University of Chinese Academy of Sciences, Beijing, 100049, China; KIZ-SU Joint Laboratory of Animal Model and Drug Development, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. Electronic address: [email protected].
PMID: 41722706 DOI: 10.1016/j.antiviral.2026.106376
Abstract

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 m6A 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.

Keywords

Antiviral compounds; METTL3 inhibitor; Onvansertib; RNA m(6)A modification; SARS-CoV-2; Vilazodone.

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