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

Area of Science:

• Virology
• Infectious Diseases
• Drug Discovery

Background:

• Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe disease with high mortality (up to 40%).
• No licensed antiviral treatments exist for CCHF, highlighting an urgent unmet medical need.
• CCHFV shares a unique "cap-snatching" RNA transcription mechanism with influenza viruses.

Purpose of the Study:

• To investigate the efficacy of baloxavir, an anti-influenza drug targeting "cap-snatching", against CCHFV.
• To develop an orally bioavailable and effective CCHF treatment by modifying baloxavir.

Main Methods:

• In vitro testing of baloxavir acid against CCHFV infection and replication.
• In vivo evaluation of baloxavir marboxil and synthesized baloxavir sodium in a lethal CCHFV mouse model.
• Assessment of survival rates and viral loads in tissues.

Main Results:

• Baloxavir acid inhibited CCHFV infection and RNA transcription/replication in cell culture.
• Baloxavir marboxil did not protect mice from lethal CCHFV challenge due to poor bioavailability.
• Baloxavir sodium demonstrated significantly improved survival rates and reduced viral loads in mice.

Conclusions:

• Baloxavir sodium is a promising candidate for CCHF treatment due to enhanced pharmacokinetic properties.
• The study identifies baloxavir sodium as a novel scaffold and mechanism for anti-CCHF therapy.
• Further optimization of baloxavir sodium may lead to a viable clinical treatment for CCHF.