Influenza Antiviral Drug Baloxavir- Indications, Mechanism of action, Side effects etc.

Baloxavir is a drug employed in the treatment of influenza virus infection. Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.

Development History

Baloxavir marboxil was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). BXA then functions as enzyme inhibitor, targeting the influenza virus' cap-dependent endonuclease activity, used in "cap snatching" by the virus' polymerase complex, a process essential to its life-cycle.

Licensed in Japan and the United States since 2018, baloxavir marboxil is the first new influenza drug class approved in 2 decades for the treatment of uncomplicated influenza infection in patients older than 12 years of age. Taken orally, baloxavir marboxil is a prodrug that prevents cap-snatching by blocking PA endonuclease activity when hydrolyzed to free baloxavir acid. A single dose is typically sufficient for clinical benefit, and efficacy is similar to, or better than, current standard-of-care.

Mechanism of Action

Baloxavir marboxil is an influenza therapeutic agent, specifically, an enzyme inhibitor targeting the influenza virus' cap-dependent endonuclease activity, one of the activities of the virus polymerase complex. In particular, it inhibits a process known as cap snatching,[medical citation needed] by which the virus derives short, capped primers from host cell RNA transcripts, which it then uses for polymerase-catalyzed synthesis of its needed viral mRNAs.[18] A polymerase subunit binds to the host pre-mRNAs at their 5' caps, then the polymerase's endonuclease activity catalyzes its cleavage "after 10–13 nucleotides".[medical citation needed] As such, its mechanism is distinct from neuraminidase inhibitors such as oseltamivir and zanamivir.

Baloxavir marboxil is unique in that it inhibits viral replication by targeting the endonuclease function encoded by the PA subunit of the viral polymerase complex. Influenza viruses have a trimeric polymerase complex composed of the PB1, PB2, and PA subunits, and the RNA-dependent RNA polymerase activity resides in the PB1 protein. The synthesis of viral mRNAs requires a host pre-mRNA to be used as a primer for viral transcription, and to achieve this the PB2 protein binds to the 5′-cap structure of host pre-mRNAs in the nucleus of the infected cell. For over two decades it was known that an endonuclease was required to cleave the captured pre-mRNA 10–13 nucleotides from the cap structure. Studies showed that inhibiting this activity strongly decreased viral replication, supporting the notion that the endonuclease function would be a good antiviral target. 

Side Effects

Common side effects following the single dose administration of baloxavir marboxil include diarrhea, bronchitis, common cold, headache, and nausea. Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir.

Baloxavir marboxil is a substituted pyridone derivative of a polycyclic family, whose chemical synthesis has been reported in a number of ways by the company discovering it, Shionogi and Co. of Japan (as well as others); the Shionogi reports have appeared several times in the Japanese patent literature between 2016 and 2019, providing insight into possible industrial synthetic routes that may be in use.