Snake venom to blood pressure drugs: the origin of ACE inhibitors

ACE inhibitors — lisinopril, ramipril, captopril, drugs that sit at the center of treating high blood pressure, heart failure, and diabetic kidney damage — came out of a Brazilian pit viper.

Researchers at the Butantan Institute were studying the Bothrops jararaca lancehead because its bite caused a sudden, severe blood pressure collapse. That work produced the discovery of bradykinin, a peptide that regulates blood pressure and inflammation in mammals. A graduate student, Sergio Ferreira, then identified that the venom contained peptides that blocked the enzyme breaking bradykinin down. When Ferreira brought those findings to a London lab, researchers realized the same enzyme also converts an inactive molecule into angiotensin 2, a potent blood-vessel constrictor. That enzyme is angiotensin-converting enzyme, ACE.

Chemists at Squibb took the smallest active venom peptide as a structural model and built captopril, the first orally effective ACE inhibitor, approved by the FDA in 1981.

Peter Attia's account of this history makes one thing plain: nobody in that chain was trying to treat hypertension. The drug class came out of field biology and basic curiosity about how venom kills. The renin-angiotensin-aldosterone system those drugs target is now among the most treated pathways in medicine.

The ACE inhibitor class — drugs like captopril, lisinopril, and ramipril that are foundational in treating high blood pressure, heart failure, chronic kidney disease, and diabetic kidney damage — traces back to a Brazilian pit viper. Researchers at the Butantan Institute in Brazil were studying the venom of the Bothrops jararaca lancehead snake because its bite caused a sudden, catastrophic drop in blood pressure. That work, beginning around mid-century, accidentally produced the discovery of bradykinin, a peptide that turns out to be a fundamental regulator of blood pressure and inflammation in mammals. A graduate student named Sergio Ferreira then found that the venom also contained peptides — bradykinin-potentiating factors (BPFs) — that blocked the enzyme that breaks bradykinin down. Carried to a London lab, Ferreira's BPFs revealed that the same enzyme also converts an inactive molecule (angiotensin 1) into a potent blood-vessel constrictor (angiotensin 2). That enzyme was angiotensin-converting enzyme, or ACE.

Chemists at the pharmaceutical company Squibb used the smallest active venom peptide as a structural model and designed the first orally active ACE inhibitor, captopril, approved by the FDA in 1981. Peter Attia's account emphasizes that no one in that 70-year chain was trying to develop a hypertension drug — the molecule fell out of field biology and basic curiosity about how snake venom kills prey. The renin-angiotensin-aldosterone system these drugs target is now one of the most heavily treated pathways in all of medicine.