HOW PFIZER DEVELOPED THE COVID FIGHTING DRUG PAXLOVID

 

Modified from a web article by Eurofins CDMO Alphora

 

“Pfizer started their paxlovid study on March 13, 2020, when they sent medicinal chemist Dafydd Owen home from his job at Pfizer in Cambridge, Massachusetts. His bosses asked him to spend the weekend thinking about what resources he would need to lead a program to develop an oral drug to fight the emerging pandemic. Owen had started working at the company’s Sandwich, England, site in 1999 and moved to the US in 2011. For the prior decade, he says, his role has been to help pick targets for medicinal chemistry programs.   In this case, he didn’t have to pick the target. Pfizer scientists knew they wanted to make an antiviral that would go after the main protease (also known as the 3CL protease) of SARS-CoV-2—the coronavirus that causes COVID-19. I

Inhibiting a viral protease has been a successful strategy for developing drugs that fight HIV and hepatitis C.  In 2003, researchers at the company had developed an antiviral, known as PF-00835231, that could block the main protease of a coronavirus that emerged in 2002 and causes severe acute respiratory syndrome (SARS). But by the time they were ready to test it in patients, the SARS outbreak had been contained. PF-00835231 is structurally similar to a peptide that binds within SARS’s main protease. That binding site in SARS is identical to the one in SARS-CoV-2, so Pfizer researchers thought the molecule could work against the new virus. Tests showed they were right.  But the molecule was destroyed in the gut and had to be administered intravenously. To make an orally viable drug the chemists had to eliminate some of the hydrogen bond donors that keep PF-00835231 in the gut.

They looked for “hydrogen bonds that we could get rid of without losing antiviral potency.” They decided to replace that portion with a cyclic amino acid that would eliminate an N–H bond. “Once you’ve made it cyclic, it still has to look like leucine (an amino acid), because the protease is expecting to see leucine at that position,” Owen says. To achieve leucine-like binding, the motif also features a fused cyclopropyl ring with two methyl groups. Computational studies suggested the structure would slot into the binding site. And there was precedent for the motif: Schering-Plough scientists had used it in the hepatitis C antiviral boceprevir.

“Making rings is kind of boom or bust in med chem,” Owen said. “You either win big or you lose big, because you’re only sampling one conformation when going to a cyclic molecule. So that conformation had better be right, or else you’re going to end up with an inactive molecule.”

On July 22, 2020, Pfizer chemists made PF-07321332—which would eventually be the active ingredient in Paxlovid.  Known as nirmatrelvir it was just one of the 20 compounds we made that week,” Owen said. “We didn’t know what we had then.”

The molecule incorporated all the strategic tweaks the chemists had come up with to make it both a potent antiviral and a compound that could be taken as a pill. On the morning of September 1, 2020 the results of the pharmacokinetic study in rats came back and the researchers knew they were on the right path.

https://cen.acs.org/pharmaceuticals/drug-discovery/How-Pfizer-scientists-transformed-an-old-drug-lead-into-a-COVID-19-antiviral/100/i3

 

Comments

Post a Comment

Popular posts from this blog

what is targeted chemotherapy

  According to AI There are about 3 billion pairs of nucleotides.   Most of the nucleotides are involved in turning a fertilized cell into a being.   2 percent of the nucleotides are genes and they direct the cells to make various proteins.    There are about 20,000 protein coding genes and each gene contains the instructions for making a single protein.   20 to 30 percent of the proteins the cell makes perform a function in the cell membrane.     One type of membrane protein is called a receptor tyrosine kinase (RTK).   it penetrates the membrane and sticks out inside and outside the cell.   When the outside of this protein is activated—a signal travels through the protein and the inside portion of the protein directs a cell to act a certain way.   It, for example, can tell a cell to grow, divide, die etc.   the outside extension of each receptor has a pocket.   When the right molecule is inserted into the poc...
Read more

?? THE SNAKE ANTIVENOM OF THE FUTURE.

  An article in the October issue Science described a new drug that could save the lives of up to 100,000 Africans.   It’s 3 years away from trials in humans but if it works—who knows.   The article claims that each year about 100,000 Africans are killed by venomous snakes and the current antivenom isn’t very effective for a number of reasons.   “This new kind of antivenom has proved protective only in mice so far. But   “It’s a potential game changer if all goes well.” To make their antivenum Laustsen-Kiel and colleagues injected mixtures of venoms from 18 African snakes into llamas and alpacas and the animals made antibodies. Their antibodies are smaller than those of horses and humans and have only one protein chain, instead of two, on each arm of the Y-shaped molecule. Each arm, dubbed a nanobody, can be separated from its base while remaining able to bind a target molecule, such as a toxin . The isolated arms lack the animal-specific sections th...
Read more

MALARIA

  ACCORDING TO THE WORLD HEALTH ORGANIZATION Globally in 2023, there were an estimated 263 million malaria cases and 597 000 malaria deaths in 83 countries. The WHO African Region carries a disproportionately high share of the global malaria burden. In 2023, the WHO African Region was home to 94% of malaria cases (246 million) and 95% (569 000) of malaria deaths. Children under 5 accounted for about 76% of all malaria deaths in the Region. Malaria  is a  mosquito-borne infectious disease     people who are bitten by infected mosquitoes often develop a “ fever ,  fatigue ,  vomiting , and  headaches , and in severe cases, it can cause  jaundice ,  seizures ,  coma , or  death . [1] [9]  Symptoms usually begin 10 to 15 days after being bitten   The current therapy is Artemisinin.   It’s discovery led to a Nobel Prize in 2015. The World Health Organization began to recommend ACTs as the front-line treatment for ma...
Read more