Ensitrelvir

Ensitrelvir
Why in news? The antiviral drug Ensitrelvir was recently in the news after the SCORPIO-PEP trial demonstrated its effectiveness in preventing COVID-19 among close contacts of infected individuals through post-exposure prophylaxis.
Ensitrelvir is an oral antiviral drug that directly targets and inhibits the Mpro  enzyme of SARS-CoV-2.
It was developed by a Japanese pharmaceutical company named Shionogi using computational chemistry and virtual screening techniques.
The drug received emergency approval in Japan in 2022 and full approval in 2024 for mild-to-moderate COVID-19 treatment.
In the recent study involving 2,387 participants, Ensitrelvir demonstrated a 67% reduction in symptomatic COVID-19 among exposed contacts.
The study found that administration within 72 hours of symptom onset in the primary patient significantly reduced the risk of infection among close contacts.
 
Background
SARS-CoV-2 produces many of its proteins as a single long polyprotein chain, which must be cut into functional proteins by viral proteases before the virus can replicate.
Two key proteases of SARS-CoV-2 are the Main Protease (M pro) and Papain-like Protease (PLpro), both of which are essential for viral replication.
Main Protease (Mpro) as a Drug Target
Mpro performs most of the protein-cleavage steps required for SARS-CoV-2 replication.
The Mpro of SARS-CoV-2 is highly similar to that of SARS-CoV-1, enabling scientists to build upon earlier research for drug development.  
An older SARS-CoV-1 drug candidate was re-engineered into Nirmatrelvir, which later became a major oral COVID-19 treatment.
Limitations of Nirmatrelvir
Nirmatrelvir is rapidly metabolised in the liver and therefore requires co-administration with Ritonavir.
Ritonavir slows drug breakdown but can interact with several commonly used heart and blood-pressure medicines.
The treatment regimen is also associated with an unpleasant bitter aftertaste in some patients.
Development of Ensitrelvir
Ensitrelvir was developed using computational chemistry and virtual screening techniques rather than conventional large-scale compound testing.
The drug directly targets and inhibits the Mpro enzyme of SARS-CoV-2.
Ensitrelvir remains in the bloodstream for longer periods and does not require an additional booster drug such as Ritonavir.
The drug received emergency approval in Japan in 2022 and full approval in 2024 for mild-to-moderate COVID-19 treatment.
SCORPIO-PEP Trial: Major Current Development
The international SCORPIO-PEP trial evaluated Ensitrelvir for post-exposure prophylaxis (PEP), which refers to preventing infection after exposure to a pathogen.
The study involved 2,387 participants who had been exposed to an infected household member.
Ensitrelvir reduced symptomatic COVID-19 incidence from 9% in the placebo group to 2.9% in the treatment group.
The trial demonstrated a 67% reduction in symptomatic COVID-19 among exposed contacts.
The presence of SARS-CoV-2 infection, regardless of symptoms, decreased from 21.5% to 14%.
The study reported a favourable safety profile for the drug.
Related topics
Viral proteases are attractive drug targets because they are indispensable for the virus but sufficiently different from human proteins.
Antiviral drug development is generally difficult because viruses depend heavily on host-cell machinery, increasing the risk of damaging healthy human cells.
Therefore, identifying viral proteins such as Mpro that are essential for replication and distinct from human proteins enables the development of targeted antiviral drugs.
Consequently, Mpro has led to the development of drugs such as Ensitrelvir
Challenges in Antiviral Drug Development
Unlike antibiotics that can target bacterial-specific structures such as cell walls, antiviral drugs are usually virus-specific and rarely broad-spectrum.
Viruses possess fewer unique biological structures than bacteria, limiting the number of safe drug targets. Drugs targeting viruses may inadvertently interfere with normal human cellular processes as viruses share many characters with the host cell.
Rapid mutation and emergence of new viral strains require continuous research and development of antiviral therapies.
Developing effective oral antiviral drugs is challenging because many compounds are rapidly metabolised by the liver.