Bruton's tyrosine kinase inhibitor BTKi-2 inhibits mpox virus and vaccinia virus infection

  • Virol Sin. 2026 Jun 19:S1995-820X(26)00100-8. doi: 10.1016/j.virs.2026.06.011.
Chen Yang  1 ,  Runchu Zhao  2 ,  Shuting Huo  1 ,  Yaqing Zhang  1 ,  Jingxi Feng  1 ,  Mingli Gong  1 ,  Lin Zhu  3 ,  Conggang Zhang  4 ,  Linqi Zhang  1 ,  Jing Xue  3 ,  Rong Zhang  5 ,  Qihui Wang  2 ,  Qiang Ding  6
Affiliations
  • 1. School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 2. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 3. Institute of Laboratory Animals Science, CAMS & PUMC, Beijing 100021, China.
  • 4. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 5. School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200433, China.
  • 6. School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
PMID: 42320797 DOI: 10.1016/j.virs.2026.06.011
Abstract

The recent global outbreak of mpox virus (MPXV) infections underscores the urgent need for Antiviral therapies against orthopoxviruses. In this study, using a high-content screening (HCS) platform based on a modified vaccinia virus Tiantan strain with GFP insertion (MVTT-GFP) under BSL-2 conditions, we screened 1513 kinase inhibitors for Antiviral activity. Among these, Bruton's tyrosine kinase inhibitor BTKi-2 emerged as a potent candidate, exhibiting IC50 of 0.535 μM against vaccinia virus (VACV) and 0.260 μM against MPXV in vitro, while maintaining low cytotoxicity. In a murine model of VACV-induced pneumonia, BTKi-2 treatment reduced lung viral loads by 90% and a significantly improved survival compared to vehicle-treated controls. Notably, mechanistic studies indicate that BTKi-2's Antiviral effects cannot be completely attributed to the inhibition of Btk or EGFR/ErbB2 signaling. These findings highlight BTKi-2 as a promising Antiviral agent in vitro and in vivo, suggesting that BTKi-2 may offer a potential avenue for future therapeutic development against Orthopoxvirus infections.

Keywords
BTK inhibitor-2; EGFR; ERBB2; High-content screening; Mpox virus (MPXV); Vaccinia virus (VACV).
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