Tuesday, January 18, 2022

How Paxlovid Works.


You are likely hearing, or will hear, a lot of news about Pfizer's anti-viral drug 'paxlovid' (nirmatrelvir or PF-07321332) given that it was approved for use in Canada as reported yesterday by the CBC's John Paul Tasker:
Health Canada has approved Pfizer's COVID-19 therapeutic for use in adults 18 and older, paving the way for the distribution of a potentially lifesaving drug at a time when the country's hospitals are overwhelmed.

Pfizer's Paxlovid is an oral antiviral treatment prescribed by a doctor and administered in pill form. It is designed to help the body fight off the SARS-CoV-2 virus, reduce symptoms from an infection and shorten the period of illness...

Paxlovid does not act by boosting the immune system against the virus, which is a good thing because that means that 'immune evasion' is not an issue. 

Instead, the drug, which Pfizer has gone to great lengths to modify so that it can be taken orally rather than intravenously, blocks the ability of the virus to make more of itself once it gets into the cells, including the cells that line the inside of our airways.

More specficially,  in Step 3 of the viral life cycle (see diagram, above, from Science magazine), paxlovid/PF-07321332 inhibits the ability of the 'main protease' (MPro) of the virus to chop up long strings of proteins that have been read out (or 'translated') from the viral RNA (Step 2) inside our own cells. 

The activity of the 'MPro' is essential for the viral life cycle to continue (Steps 4 and 5) because the chopped up chunks of protein from the original long string are the functional bits of the virus that allow it to make more of itself (i.e. to 'replicate') so that it can be released from your own cells (Step 6) such that it can then infect more of your own cells or be released from your airways as aerosols which can infect other people. 

The take home message.... When you whack 'MPro' with paxlovid/PF-07321332 you make less virus, which means you have less viral load in your body. As a result, you don't get as sick and, it appears, you are also less infectious.

Thus, there are real benefits here that include:
1) you can take it easily by mouth.

2) you don't have to worry about immune escape (or, in most cases, the state of your own immune system) for it to work.

3) According to the clinical trial data released by Pfizer so far, it will work for at least five days after a virally infected person becomes symptomatic which is a decent window of time to get the drug into people in real world settings.

But could the virus mutate so that paxlovid stops working?

Well, that's possible, although, unlike the spike protein (which forms the little red bits sticking out of the virus that the virus uses attach to and enter into cells, Step 1 above) where there are many mutations, there is only one mutational change in MPro in the omicron variant. However, that could change/accelerate when paxlovid treatment causes selection pressure for variants that could escape drug effectiveness. 

Ultimately, issues about protease inhibitor/paxlovid resistance due to mutation could be overcome by developing additional drugs that attack other molecular choke points in the viral cycle. This is a strategy that has been used successfully in HIV treatment, although there things are different in that the treatments are chronic/go on for long periods of time which, at least so far, is not the goal of acute paxlovid treatment against SARS-CoV-2 (i.e. you take it twice a day for five days). Regardless, there are other drugs in the pipeline, including Merck's 'molnupiravir' which works by blocking a different  enzyme called RNA dependent RNA polymerase (RdRP) that is critical for making new copies of the viral genome (see Step 4 in the diagram above).

There is actually a second drug that you take with PF-07321332 in Pfizer's treatment called 'ritonavir' which acts by decreasing the activity of a molecule in your own body (including in the intestines and the liver) called cytochrome 3A4. Normally, cytochrome 3A4 acts to break down/metabolize drugs/foreign agents, so here ritonavir decreases the breakdown of paxlovid. As a result, paxlovid levels remain higher for a longer in our bodies which makes it more effective against the virus. 
Regarding Merck's 'molnupiravir'...It doesn't appear to be as effective in clinical trials as Pfizer's treatment, at least on its own. There are also some concerns that it might speed viral mutation rates because of the way it works (i.e. it mucks up the ability of the virus to copy its own RNA which is where everything, including mutations, are coded).



Bruce Mitchell said...

Is the virus replication retardant mechanism somewhat similar to such drugs as valacyclovir and how it works on the cold sore and shingles virus?

Lulymay said...

Just had to let you know how much I appreciate your explanations of scientific data for those of us who are more comfortable working in the accounting field.
While I will never understand the detail, I do get the gist of all this complicated stuff you are obviously so comfortable with.

The "other half" in my life suffered blood clots 22 years ago while we were heading for our first winter in the sun down south. The ER doctor told me he had the clots in 3 of the 4 lobes and the lung specialist opined that he didn't know why he was still alive. Being a heavy smoker for 30 years (had quit several years earlier) added to their amazement. He has also had 3 bouts of pneumonia over the years, so you get the picture.

When Covid became a very real concern, our family Dr. said to stay home and let your family do your grocery shopping because this is serious! So since then, we have adhered to all advice from people such as Dr. Bonnie as well as any others who know the medical world far more than we ever will.

This development of an oral method of providing further kinds of protection is welcome news to us, and your detailed explanations to folks like us is very much appreciated and as someone (me) who is scared to death at the sight of a "needle" (me), I'm even happier with the progress that pharmaceutical companies are working on all things "pandemic". Thank you!!

Gordie said...

Wow...the human body is an unbelievably complex piece of machinery. I wish I had gone into biochemistry instead of mathematics...it's fascinating stuff.

I heard that a treatment of paxlovid costs $700...compared to about $20 for a dose of vaccine. We should use it only when necessary...

RossK said...


Your other half is most definitely in that high risk group - you all are doing the right thing!

Hope I've been able to make sense of some of the biology of all this stuff for you.



It's really interesting - when I trained to become a biologist quite a while ago now math rarely entered the picture. Now, it's everywhere and someone who can do both is worth their weight in gold. Good examples of this are some of the really sharp folks who are part of the local COVID modelling group.

The price thing is certainly an issue and, of course, as the Pfizer treatment is on patent they can charge through the nose...It's also going to be restricted, at least initially, by supply. My understanding is that the province is only expecting to receive a few thousand courses of treatment in the short-term.


You always make me work for my (non-existent) money!

Valacyclovir inhibits the ability of a number of DNA-containing viruses to make more of their own DNA ('replication'). Thus, if the diagram in the post were modified for a DNA virus it would act at step 4. Ultimately, however, the result is the same - less virus produced and released.


Graham said...

Much as Lulumay said, thank you for the somewhat simpler terms of explanation. Except I’m not even at an accounting level and so quickly find myself in the deep end. I get the gist of it though and do appreciate your efforts.
My dad’s name is Gordon too and he is good at math. Unfortunately none of it passed to me via the DNA.
I am happy we have this treatment available but will still try to avoid it as a first defence. I’m all boostered up now.
I wonder if those who feel there wasn’t enough time and testing for the vaccine will consider this treatment to have also been rushed through the development and approval process.

RossK said...


I take your point about skepticism of some. However, this went through the US FDA approval process first and then Health Canada. There is real rigour in both processes.

Also, as I noted in the post, and as Bruce's question makes clear, this isn't a brand new approach. It's a tweak to an approach that has been used successfully with other antivirals. In the specific case of paxlovid it's actually a modification of a compound that was first developed to be used against the original SARS virus.

The deep-end of a lot of this stuff is often in the weird names/nomenclature. Conceptually, it's really pretty simple. The virus has to stick to and then be brought into cells (the spike protein helps with that). Once in the cell the viral genetic code/RNA is used to make long ribbons of protein. The main protease (that paxlovid targets) then chops up the long ribbons into little bits of functional protein that are required to make and package up a bunch of new viral particles that are then released from the cell.