It’s OK, Corn Snakes Aren’t Venomous

My son recently turned 11 and for his birthday, he asked for a snake. Much to my surprise, it’s a real pleasure living with a snake. Ralph’s a hatchling corn snake, about a foot long. When you hold him, he wraps his tail around your little finger. It’s like having your hand held by a small child.

My unusual response to “How was your weekend?” -

“I bought a snake!” frequently sparked a similar reaction -

“Eh - is it poisonous?”

Would I have bought a poisonous snake for my son’s birthday?

No, of course not. But it made me wonder about snake venom and whether components of it have been re-purposed for medicinal uses.

I have spent almost all of my research career hunting for a cell line sensitive to the hormone Angiotensin II (Ang II) - my nemesis, as I have come to refer to it. Ang II causes a narrowing of blood vessels, increasing blood pressure since there is less space in which the same amount of blood can flow. When cells are immortalised so that they can be grown in the lab, they frequently lose their Ang II receptors - hence my quest. In the body, Ang II is made by the liver as the precursor Angiotensinogen. This molecule is cleaved by Renin, made by the kidneys in response to renal sympathetic nerve activity, lowered blood pressure or dehydration. Renin activity removes two amino acids, converting Angiotensinogen into Angiotensin I.

Angiotensin-coverting enzyme (ACE) in turn removes two further amino acids to make the bioactive hormone Angiotensin II. Angiotensin II acts on vascular smooth muscle cells to make blood vessels constrict, and on proximal tubule cells of the kidney to promote sodium uptake and increase blood plasma volume. In this way, Ang II serves to increase blood pressure by making blood vessels narrower and increasing the amount of blood travelling through them.

The regulation of blood pressure is a complicated process, with many players, positive and negative regulators. Researchers working on circulatory shock and the proteolytic enzymes present in snake bites observed that a bite from a South American pit viper jararaca (Bothrops jararaca) caused a significant drop in blood pressure. Further investigation led to the discovery of Bradykinin in 1948, from the blood of animals after the addition of this snake’s venom. Bradykinin also occurs naturally in the human body, having an opposite action to Ang II, dilating blood vessels and producing a sudden drop in blood pressure.

What I think is really interesting is that the venom of the pit viper doesn’t just contain Bradykinin, but also nine other proteins found to increase the effects of Bradykinin. ACE, which we met above, activates Ang II to increase blood pressure, but it also degrades Bradykinin to prevent its blood pressure-lowering ability. These nine other proteins in pit viper venom actually inhibit ACE as a second line of attack against the cardiovascular system - they were later termed Bradykinin-potentiating factors (BDFs). If the body had successfully broken down the Bradykinin delivered by the venom, then the venom has an attack for that too, inhibiting ACE. Genius.

Captopril was the first drug approved by the U.S. Food and Drug Administration (F.D.A.) (1981) and European Medicines Agency (E.M.A.) (1984) as an anti-hypertensive drug that targeted ACE; the first ACE inhibitor. First synthesised in 1975 at U.S. drug company, E.R. Squibb & Sons Pharmaceuticals (now Bristol-Myers Squibb), captopril is a small, synthetic molecule based on the WAP (Tryptophan-Alanine-Proline) motif present in the pit viper BDFs - the motif that binds to and inhibits ACE. Captopril’s action is two-pronged, increasing the concentration of the vasodilator Bradykinin by preventing its degradation by ACE, and also preventing the action of ACE to release the vasconstrictor Angiotensin II from Angiotensin I, limiting its ability to increase blood pressure.

Consequently, captopril and its derivatives have been a major breakthrough in the treatment of hypertension, and also in the treatment of chronic kidney disease. These drugs have saved countless lives, all because of the venom of a snake.

Bothrops jararaca

References

Lüddecke et al., 2023 Venom biotechnology: casting light on nature’s deadliest weapons using synthetic biology Front. Bioeng. Biotechnol. 11:1166601.

Oliveira et al., 2022 The chemistry of snake venom and its medicinal potential Nat. Rev. Chem. 6(7):451-469.