The recent success of Ensitrelvir at preventing COVID-19 is a milestone in a drug quest that began with a singular development at the start of the pandemic.

In January 2020, the full-length genome sequence of a strain of the SARS-CoV-2 virus was posted on an online discussion forum for virologists. The sequence revealed that SARS-CoV-2, like its relative SARS-CoV-1, keeps most of its proteins as one long chain. The individual proteins are then cut from this chain and released by enzymes called  proteases.

Inconvenient guests

SARS-Cov-2 has two proteases called the main protease (M^pro), which does most of the cutting, and the Papain-like protease (PL^pro) which cuts the three sites at one end of the chain that the M^Pro does not process. Almost immediately after the genome sequence was published, scientists knew that both these proteases were attractive drug targets.

Viruses are made of the same material as their host cells. The viral membrane is derived from the host’s cell-membranes, and the viral proteins are made by the host cell itself. This makes antiviral drug development more challenging than developing drugs against, say, bacteria.

Most other pathogens are living cells with several features that humans do not have. For instance, bacteria have a rigid cell wall. Antibiotics can be made that block the synthesis of this cell wall, and those antibiotics will affect only the bacteria without affecting humans much. Also, that antibiotic will work against most classes of bacteria because most of them have a cell wall.

Viruses, however, do not offer such conveniences. Since they rely heavily on the host cell’s machinery, drugs that attack the virus can also risk damaging healthy cells. As a result, there is no broad-spectrum antiviral drug. Instead, scientists usually need to design drugs specifically for a particular virus, or if they are lucky, for a group of closely related viruses that share similar proteins.

A drug shelved

This is why viral proteins that are essential for the virus while being significantly different from human proteins are extremely valuable drug targets. Both SARS-CoV-2 proteases fit this description perfectly. The virus cannot replicate without them and human cells do not have identical versions of these enzymes. Among them, M^pro was the first choice for most researchers.

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When scientists sequenced the SARS-CoV-2 genome, those at Pfizer realised its M^pro protease was very similar to that of SARS-CoV-1. It so happened that a few years ago, they had developed an intravenous drug called PF-00835231 targeting the M^pro of SARS-CoV-1. However, when the virus vanished in early 2004, they shelved the compound thinking they would not need it again.

In 2020, knowing that the two M^pro proteinsare similar, they set out to re-engineer PF-00835231 because an intravenous drug would be useless at controlling a pandemic the size of COVID-19, where most people would not get admitted to a hospital. After a few months, they developed Nirmatrelvir. By the time they finished clinical trials, it was already late 2021.

Different approach

However, while Nirmatrelvir was very effective as an oral drug, it had major problems. First, it was metabolised very quickly by the liver. To keep it in the bloodstream for longer, scientists had to add a second drug, Ritonavir, to the regimen to slow down the liver’s ability to metabolise Nirmatrelvir. The problem? Ritonavir had dangerous interactions with common heart and blood pressure medications. And then there was the added side effect of a bitter aftertaste.

Around the same time that Pfizer was engineering Nirmatrelvir, a Japanese pharmaceutical company named Shionogi took a different approach to targeting M^pro. Instead of making and testing millions of potential drug candidates, they decided in the interest of time that they would use computational chemistry to ‘virtually’ screen compounds.

Using the structure of the M^pro protease, they simulated thousands of molecules that would bind the protease and inactivate it. This approach quickly identified a promising molecule that they could then test further. Then they partnered with the International Institute for Zoonosis Control at Hokkaido University for testing. With a few tweaks, they came up with a molecule that stayed in the blood for a long time without the need for additional drugs and did not have the bitter after-taste. They called this molecule Ensitrelvir.

SCORPIO-PEP trial

Ensitrelvir was granted emergency approval in Japan for use in November 2022 to treat mild-to-moderate COVID-19. In early 2024, it was granted full authorisation for regular use. Now, a new paper in the New England Journal of Medicine has reported that it can also be used for postexposure prophylaxis — to prevent infection after exposure to the virus.

The international study, called the SCORPIO-PEP trial, involved 2,387 participants, all of whom were exposed to an infected household member. They were assigned to a test or a placebo group at random. Participants in the test group received Ensitrelvir and the control group received the placebo. 

The results revealed that Ensitrelvir lowered the incidence of symptomatic COVID-19 from 9% in the control group to 2.9% in the group that took the drug — a drop of 67%. The trial scientists showed that irrespective of whether symptoms developed, the presence of SARS-CoV-2 in the contacts was reduced from 21.5% to 14%. Importantly, the drug maintained a good safety profile in the study. The authors concluded that giving Ensitrelvir to contacts within 72 hours of a primary patient showing symptoms could effectively prevent COVID-19.

SARS-CoV-2 today does not pose the threat it once did but the importance of Ensitrelvir extends well beyond COVID-19. Betacoronaviruses have now caused three major outbreaks in just over two decades: SARS-CoV-1, MERS-CoV, and SARS-CoV-2. Drugs like Ensitrelvir provide scientists with a valuable starting point against this entire sub-family of viruses, possibly allowing humankind to respond more quickly when the next virus will inevitably emerge.

Arun Panchapakesan is an assistant professor at the Y.R. Gaitonde Centre for AIDS Research and Education, Chennai.