The Amazon rainforest, snake venom, and the discovery of ACE inhibitors

This is a story about where drugs actually come from — not from chemistry sets or rational drug design at a whiteboard, but from the patient observation that nature has already solved problems the human body faces, sometimes in the most unexpected places.

The Brazilian pharmacologist Maurício Rocha e Silva had identified bradykinin in the 1940s — a peptide produced during inflammatory responses that caused smooth muscle contraction and vasodilation. By the early 1960s, researchers understood that something in viper venom potentiated bradykinin's effects, making the hypotensive response more pronounced. The task of identifying what that something was fell to a young pharmacologist named Sérgio Ferreira, who was working in Rocha e Silva's lab in São Paulo before traveling to the United Kingdom to work with John Vane at the Royal College of Surgeons. Ferreira isolated a fraction from Bothrops jararaca venom that he called BPF — bradykinin-potentiating factor. It was not one compound but a mixture of peptides, each with slightly different sequences, each blocking an enzyme that degraded bradykinin before it could complete its vasodilatory work. The enzyme being blocked — what Ferreira's peptides were targeting — was angiotensin-converting enzyme, or ACE.

ACE had a second job beyond degrading bradykinin. It was also the enzyme that converted angiotensin I into angiotensin II, the potent vasoconstrictor that drives much of the renin-angiotensin system's blood pressure regulation. Block ACE, and two things happen simultaneously: bradykinin is preserved, extending its vasodilatory effect, and angiotensin II production is reduced, removing a major vasoconstrictor signal. The net effect is blood pressure reduction. The viper venom peptides were teaching researchers how a key regulator of blood pressure actually worked — by providing a specific, high-affinity inhibitor that evolution had refined over millions of years for the precise purpose of disrupting mammalian physiology.

Ferreira brought this work to the Squibb Institute for Medical Research in New Jersey in 1970, where he collaborated with David Cushman and Miguel Ondetti. The challenge was that the venom-derived peptides — teprotide was the most studied — were active only when injected. Administered orally, they were degraded in the gut before reaching the circulation. The peptide chemistry was too fragile. What Cushman and Ondetti needed was a molecule that captured the structural logic of the venom peptides — their ability to sit in ACE's active site and block it — but that could survive the oral route. They modeled the ACE active site, reasoned about what a small, orally available molecule would need to look like to fit it, and synthesized captopril. It was not a peptide. It was a small molecule that imitated what the peptide was doing at the enzyme. The 1977 publication of its structure and mechanism was followed by FDA approval in 1981 for hypertension and in 1983 for heart failure. Within a decade, ACE inhibitors had transformed the pharmacological management of cardiovascular disease. Enalapril, lisinopril, ramipril, and others followed. Today, ACE inhibitors are among the most widely prescribed drugs in the world. The intellectual lineage runs directly from a Brazilian pit viper to a pharmacist's shelf.

The lesson encoded in this story is not sentimental. It is structural. Venoms are not random toxins — they are highly evolved peptide libraries, refined by natural selection over geological timescales to be maximally effective at disrupting specific physiological systems in prey and predators. A venom that kills by hypotension contains peptides with exquisite affinity for the molecular targets that regulate blood pressure. A venom that kills by neurotoxicity contains peptides that bind with precision to ion channels or acetylcholine receptors. The evolutionary pressure to be lethal or incapacitating has produced, as a byproduct, some of the most specific and potent peptide ligands for mammalian biology that exist anywhere in nature. This makes venoms, from a drug discovery standpoint, extraordinarily rich sources of molecular starting points — leads that have been pre-validated by millions of years of selection for biological effect.

The cone snail, Conus magus, provided the second major example. Cone snails are marine gastropods that hunt fish by firing a harpoon-like tooth loaded with venom into their prey. The venom paralyzes the fish in seconds through a cocktail of conotoxins — small disulfide-rich peptides that target voltage-gated ion channels and nicotinic acetylcholine receptors with remarkable specificity. Researchers at the University of Utah, particularly Baldomero Olivera and his lab, began systematically characterizing conotoxins in the 1970s and 1980s. One of them, omega-conotoxin MVIIA from Conus magus, blocked a specific voltage-gated calcium channel (N-type, Cav2.2) that is expressed predominantly in pain-transmitting neurons. It was a highly targeted analgesic mechanism — blocking pain signaling at a specific channel type rather than broadly suppressing the central nervous system the way opioids do. The synthetic version of this peptide became ziconotide (Prialt), FDA-approved in 2004 for severe chronic pain in patients who had failed other treatments. It must be delivered intrathecally — directly into the spinal fluid — because it doesn't cross the blood-brain barrier. It is not a mass-market drug for this reason. But it is an FDA-approved medication derived directly from a cone snail's venom peptide, demonstrating that the cone snail had, in its evolutionary arms race with fish, identified a pain pathway that human medicine could use.

The Gila monster example sits at the center of the GLP-1 story that has become the Ozempic and Wegovy story. Exendin-4 is a 39-amino-acid peptide found in the saliva of the Gila monster, Heloderma suspectum. It shares structural similarity with glucagon-like peptide-1 and activates the GLP-1 receptor, but with much greater resistance to degradation by the enzyme DPP-4 that rapidly clears endogenous GLP-1. John Eng at the Veterans Affairs Medical Center in the Bronx identified exendin-4 in 1992 and patented it for diabetes treatment. Amylin Pharmaceuticals licensed the compound, developed it into exenatide, and it received FDA approval in 2005 as the first GLP-1 receptor agonist for type 2 diabetes. Exenatide is the direct pharmacological ancestor of liraglutide, semaglutide, and the entire GLP-1 class that now dominates both diabetes and obesity treatment. The Gila monster, which evolved exendin-4 for reasons that likely relate to its own metabolism — it eats infrequently and stores large amounts of energy — inadvertently provided the structural template for a drug class that will reshape global metabolic medicine.

The scorpion venom research is earlier in translation but follows the same logic. Chlorotoxin, a 36-amino-acid peptide from Leiurus quinquestriatus, the deathstalker scorpion, selectively binds to chloride channels overexpressed in glioma cells with a specificity that has made it interesting as both a diagnostic agent and a potential drug delivery vehicle for brain tumors. Labeled versions are in clinical trials for intraoperative tumor visualization — a literal tool for surgeons to see where brain tumor tissue ends and healthy tissue begins, derived from a scorpion's venom peptide. The spider venom research includes psalmotoxin from a tarantula species, which blocks acid-sensing ion channels in pain pathways, and has attracted attention for analgesic development.

There is an ethical thread running through this entire history that rarely appears in the clinical literature. Many of these discoveries were enabled by indigenous knowledge and traditional practices that pointed researchers in the right direction. In the Bothrops jararaca case, the initial observation that pit viper bites caused hypotension came from observations by people in the Amazon region who had been living with this snake for generations and whose understanding of its effects was part of local knowledge about medicinal and toxic plants and animals. The formal biochemical characterization came from institutions in São Paulo and London and New Jersey, and the intellectual property — and the enormous commercial value — resided entirely with those institutions. Ferreira, at least, had personal knowledge of the region and its biology. The field more broadly has navigated this unevenly. The Convention on Biological Diversity, adopted in 1992, and its Nagoya Protocol, adopted in 2010 and entering into force in 2014, established frameworks for benefit-sharing with source countries and communities when biological resources are used for commercial development. The implementation has been inconsistent. Research institutions and pharmaceutical companies have not uniformly returned value to the communities or countries whose biological resources and, in many cases, whose traditional knowledge enabled the discoveries that produced these drugs.

The current state of venom-derived drug discovery is more systematic than it was when Ferreira was running extractions in a 1960s laboratory. High-throughput sequencing can now characterize the full peptide content of a venom sample rapidly. Computational tools can model which peptides are likely to bind which molecular targets. Synthesis technology can produce and modify peptide candidates at speeds that would have been unimaginable twenty years ago. The venom libraries that are now being characterized — deep-sea cone snails, Amazonian arthropods, Australian snakes, African scorpions — represent a natural pharmacopeia of extraordinary depth that is only beginning to be read systematically.

What venom pharmacology teaches about drug discovery is something more fundamental than a set of interesting case histories. It teaches that the search for molecules with specific, high-affinity biological activity need not begin from scratch. Biology has been running an evolutionary optimization process for hundreds of millions of years, and the results of that process — in the form of venoms, defensive secretions, hormones, and other biologically active compounds — are scattered across the natural world in organisms that solved problems with solutions we haven't fully characterized. Captopril came from a snake. Ziconotide came from a snail. Exenatide came from a lizard. The drugs in development from scorpions and spiders and deep-sea mollusks will come, if they come at all, from the same observation that Ferreira made in the 1960s: that something in nature had found, through a process much longer and more exhaustive than any pharmaceutical program, a key to a biological lock that medicine needed to open. The research task is not to invent these solutions. It is to find them.