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Tue Apr 6, 2021, 05:43 PM

Pfizer has developed a protease inhibitor for the treatment of infected CoV-Sars-2 patients.

I attended a lecture today at the ACS meeting by Dr. Daffyd Owen of Pfizer about which I will make a brief comment.

Years ago, when the protease inhibitors for HIV were being developed, one interesting thing about them was that they were designed to dock in a protease - a protein which cleaves larger proteins - at a specific sequence, bonds between the amino acid aspartic acid (ASP) and phenylalanine (Phe). Interestingly there are no mammalian enzymes that cleave at this sequence, making targeting much easier.

The SARS-CoV-2 RNA transcribes a protease also not found in mammalian species, which cleaves exclusively at residues of glutamine, (Gln). A widely used enzyme in analytical chemistry and mammalian stomachs is trypsin, which cleaves are arginine (ARG) and lysine Lys residues.

Dr. Owen walked us through the medicinal chemistry for the development of PF-7321332, which is designed to block the pocket of the unique SARS-CoV-2. It was simply beautiful. The work involved 210 Pfizer scientists working around the clock to produce a compound entering the clinic in 11 months, unprecedented speed!

The work built on work conducted at Agouron - a company acquired by Pfizer - to develop one of the protease inhibitors for HIV, nelfinavir. (I was involved in the scale up of this compound, peripherally.)

What is interesting is that the dose (tid, 3 times a day) is "only" on the order of 300 mg, making scale up somewhat simpler than it was for the HIV protease inhibitors which had higher doses.

Interestingly, to prevent CYP metabolism, the drug may be administered with ritinovir, a treatment for HIV, to saturate the CYP enzyme.


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Reply Pfizer has developed a protease inhibitor for the treatment of infected CoV-Sars-2 patients. (Original post)
NNadir Apr 6 OP
WheelWalker Apr 6 #1

Response to NNadir (Original post)

Tue Apr 6, 2021, 05:53 PM

1. Love your posts. Thank you.

Science matters.

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