#401 ‒ How curiosity transforms medicine: extraordinary discoveries that changed modern healthcare

“Now ACE had previously been discovered, but the identification of a potent ACE inhibitor caught the attention of chemists at Squibb. The venom peptides themselves were not viable drugs.”

“from the Gerarica venom and used it as their structural lead and designed a small, orally active molecule that inhibited ACE, in the same way that venom peptide did. This is conventionally remembered as one of the earliest examples of rational, mechanism-based drug design.”

“They called the molecule captopril, and it was approved by the FDA in 1981 as the first oral ACE inhibitor in clinical use. And captopril begat enalapril, lisinopril, ramipril, and the rest of the ACE inhibitor class, and conceptually began the angiotensin regime. They were the main receptor blockers, losartan, valsartan, and so on.”

“from a jellyfish. Statins come from a fungus growing on rice. The ACE inhibitor class came from a snake whose venom kills by dropping blood pressure. PCR, and by extension, essentially all modern molecular biology, came from a microbe in a Yellowstone hot spring.”

“for the treatment of type 2 diabetes. It was the first GLP-1 receptor agonist ever brought to market. And then the floodgates opened. Exendin-4 was a foreign Gila monster peptide, developed immune responses to the therapy.”

“length, GLP-1 signaling also suppresses appetite, slows gastric emptying, and changes how the brain weighs reward signals around food. Subsequent drugs were not direct Exendin-4 analogs, but modifications of the native human GLP-1 sequence engineered to reduce immunogenicity, increase half-life, and in some cases, add alternative targets in addition to GLP-1.”

“We now have liraglutide and semaglutide, along with terzepatide, which adds GIP agonism in addition to GLP-1. We've talked about these drugs at length, and we'll continue to talk about them as the science develops. Suffice it to say, these drugs are reshaping medicine in real time. They're reshaping the treatment of type 2 diabetes, and they're reshaping the treatment of obesity.”

“modern molecular biology, came from a microbe in a Yellowstone hot spring. CRISPR, the foundation of modern gene editing, came from the genome of a salt pond organism. And the GLP-1 class of drugs came from a desert lizard that's hardly known outside of trivia. With the exception of statins, the original scientist was not trying to cure a disease.”

“pravastatin, atorvastatin, rosuvastatin. The entire class of drugs that by any reasonable estimate has prevented millions of cardiovascular events and millions of premature deaths.”

“of rational, mechanism-based drug design. They called the molecule captopril, and it was approved by the FDA in 1981 as the first oral ACE inhibitor in clinical use. And captopril begat enalapril, lisinopril, ramipril, and the rest of the ACE inhibitor class, and conceptually began the angiotensin regime.”

“and conceptually began the angiotensin regime. They were the main receptor blockers, losartan, valsartan, and so on. The renin-angiotensin-aldosterone system is now one of the most heavily drugged pathways in all of medicine.”

“small molecules designed to poison, disable, or starve their bacterial competitors. We already had one famous example. Penicillin, discovered by Alexander Fleming, is exactly that kind of weapon, a chemical that a fungus uses to kill bacteria.”

“pravastatin, atorvastatin, rosuvastatin. The entire class of drugs that by any reasonable estimate has prevented millions of cardiovascular events and millions of premature deaths.”

“From Lovastatin, you eventually get Simvastatin, pravastatin, atorvastatin, rosuvastatin. The entire class of drugs that by any reasonable estimate has prevented millions of cardiovascular events and millions of premature deaths.”

“and conceptually began the angiotensin regime. They were the main receptor blockers, losartan, valsartan, and so on. The renin-angiotensin-aldosterone system is now one of the most heavily drugged pathways in all of medicine.”