Discovery of baloxavir sodium as a novel anti-CCHFV inhibitor: biological evaluation of in vitro and in vivo

Kai Liu; Liushuai Li; Yajie Liu; Xi Wang; Jia Liu; Jiang Li; Fei Deng; Runze Zhang; Yiwu Zhou; Zhihong Hu; Wu Zhong; Manli Wang; Chun Guo

doi:10.1016/j.antiviral.2024.105890

Discovery of baloxavir sodium as a novel anti-CCHFV inhibitor: biological evaluation of in vitro and in vivo

Antiviral Res. 2024 Apr 22:105890. doi: 10.1016/j.antiviral.2024.105890. Online ahead of print.

Authors

Kai Liu¹, Liushuai Li², Yajie Liu³, Xi Wang³, Jia Liu³, Jiang Li³, Fei Deng³, Runze Zhang⁴, Yiwu Zhou⁵, Zhihong Hu⁶, Wu Zhong⁷, Manli Wang⁸, Chun Guo⁹

Affiliations

¹ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
² State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China.
⁴ National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
⁵ Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430010, China.
⁶ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China. Electronic address: huzh@wh.iov.cn.
⁷ National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: zhongwu@bmi.ac.cn.
⁸ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China; Hubei Jiangxia Laboratory, Wuhan, 430200, China. Electronic address: wangml@wh.iov.cn.
⁹ School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: chunguo@syphu.edu.cn.

PMID: 38657838
DOI: 10.1016/j.antiviral.2024.105890

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called "cap-snatching" is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the "cap-snatching" mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization.

Keywords: Bunyavirus; CCHFV; baloxavir; cap-snatching; drug repurposing.