Very cool paper discussed on TWIV #829 on Youtube. It's about the history of Pfizer's Paxlovid. Seems it's original form was developed almost 20 years ago for SARS1! Development stopped because SARS1 died out and there was nobody to test it on (or to pay for it). When the current pandemic started, researchers pulled it of the dusty shelf and had another look at it. The cool thing is that the viral protease it blocks cuts up corona virus mega-proteins at a specific sequence location. Human proteins don't have any such sequence or such a protease! They went through six different iterations finding a molecule that would retain the original protease inhibitor function, and yet be well absorbed orally. The sixth one did the trick, but in monkeys they found it was inactivated by a cytochrome enzyme in the gut, so they did not get good serum levels. Ritinovar was known to inactivate that cytochrome enzyme, so they tried adding it. It worked! They got very high serum levels. (That's why Ritinovar is used to protect HIV protease inhibitors.)
Then they had to check it for safety. Apparently it does not react with ANY human biochemistry. They were required to give monkeys and rats ridiculously high doses, and found zero adverse effects. Then they ran human drug trials, and it was fantastically effective (given early, of course) with no adverse effects reported. The FDA told them to stop their Phase II/III trials and give the controls the drug, because it worked so well it was unethical to have a control group!
One very nice serendipity: It works against every corona virus, including SARS1, MERS, and all of the corona common cold viruses. And very likely will work against any future corona virus spillover. It's also MUCH easier to make in bulk than vaccines or MABs, and the pills have no special handling requirements. Vaccines are going to be with us for a long time, but this drug will make MABS much less necessary.
Interesting factoid: Ivermection can block the same protease, but it's very hard to get it's levels in infected cells high enough to do that without killing the patients. The fact that this drug has zero interactions with human biochemistry makes it much much safer. Ivermectin interacts with a bunch of stuff, which it's proponents claimed was great but actually causes problems.
