There are more than 200,000 venomous animal species known to science. From a global perspective venomous snakes are most often encountered due to habitat overlap. Unlike many venomous species, snakes primarily target warm-blooded animals and inadvertently this can include us. We all seemingly have a pathological fear of snakes. I certainly do! The Book of Genesis tells us that it is a serpent that triggers the expulsion of Adam and Eve from the Garden of Eden. Even in nature’s realm death by envenoming (or poisoning) or constriction feels like a grisly end. We can all imagine a 30-foot South American anaconda swallowing an entire wild boar headfirst. Hats off to the anaconda, I get indigestion just eating a modest portion of chicken madras!
Snake Venom can Hold between 30-100 Toxins
Like it or not snakes are found throughout most of the world, even including oceans, and have evolved a plethora of highly effective toxins and methods of delivery. From an evolutionary perspective venom is a clever strategy designed to immobilise prey. Snake bites worldwide are a public health issue and the statistics tell the tale. According to the World Health Organisation (WHO) there are roughly 5.4 million snakes bites each year resulting in about 1.8-2.7 million cases of envenomings. Rough estimates suggest that these cases result in up to 137,00 mortalities with up to three times more permanent disabilities resulting from limb amputations. But snakes are also now making their mark on humanity by helping create lifesaving drugs.
In general, the biochemical mechanisms of most venoms are to cause paralysis and hypotension (decrease in blood pressure); properties that are extremely useful for modern day medicine. Any one venom can contain between 30 to 100 toxins. Each specific toxin is very selective when attaching to its target within a host. Toxins have remarkable specificity as they have evolved for millions of years to target a specific receptor. From a pharmacological point of view this specificity implies that once one toxin is isolated it has very few unwanted side effects. So far seven drugs derived from animal venom have been approved by the Federal Drugs Administration (or FDA) in the United States. There are also ten more in clinical trials and even more in pre-clinical stages awaiting tests for safety and then trials in humans. PubMed is a free online search engine accessing 30 million citations for biomedical literature which I use for research. At present, according to the PubMed database, more than 1000 articles devoted to the study of venoms are published annually, and the total number of publications is more than 40,000. About half of these publications deal with snake venom.
Snake venom offers a bewildering number of possible ‘lead molecules’ (this reference reviews some of them) due to the plethora of biochemical and pharmacological activities. Their applications include a wide array of possibilities such as antihypertensive (lowering of blood pressure), anticoagulant, antimitotic (blocks cell growth e.g. cancer therapy) and antibacterial therapies, pain management and treatment of neurological disorders. In the ancient world snakes often symbolized immortality or eternal youth because of their skin-shedding ability. In the modern age we also are now beginning to appreciate that their venom harbours toxins that could help prolong life. From a pharmaceutical perspective it is the array of novel and interesting molecules that act on the cardiovascular system that have been of most interest to date. Many of these lead molecules are proteins that lead to a reduction in blood pressure (i.e. they are hypotensive). For this we have the Brazilian pit viper to thank!
The Discovery of ACE Inhibitors from the Brazilian Pit Viper
One of the most significant recent advances in cardiovascular pharmacology was the discovery of angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors are based on the first drug developed from snake venom called ‘Captopril’. They are now used to treat more than 40 million people worldwide. Captopril was designed and based from a small protein called ‘bradykinin potentiating peptide’. This was isolated from the venom of our friend the Brazilian Pit viper (Bothrops jararaca). The species is endemic to South America and it is the best-known venomous snake in the heavily populated areas of south-eastern Brazil. It is responsible for more deaths in South America than any other snake. Local tribes are said to have used its venom on their arrow tips to induce blood loss and shock, hence perhaps its nickname as the ‘arrowhead viper’. The snake uses its venom to make its prey lose consciousness from a drop in blood pressure before swallowing them headfirst like many snakes! Based on local knowledge, scientists from the UK and US began looking at the venom from the pit viper and discovered this key molecule in 1965. Captopril was approved by the FDA in 1981 and it pushed the idea that venoms could be used to create modern medicines. It was then subsequently patented and manufactured by a company now known as Bristol-Myers Squibb
ACE inhibitors work by stopping your body from producing angiotensin II (a ‘vasoconstrictor peptide’) which has the effect of constricting blood vessels, thus raising blood pressure. Angiotensin II also triggers the release of a hormone called aldosterone from our adrenal glands. Aldosterone plays a central role in the regulation of blood pressure by influencing our kidneys and our colon to reabsorb more sodium (or salt) into our blood stream. This leads to an increase in water absorption and blood volume. ACE inhibitors are approved for the treatment of high blood pressure (hypertension), though they can be prescribed for some types of congestive heart failure and cardiovascular and kidney diseases. Typically, hypertension is a key factor is almost half of cardiovascular related cases making it a huge public health issue. A worldwide health review in 2010 suggested that 31% of adults were affected by high blood pressure (or hypertensive).
Two of the most common Anti-coagulants come from the Dusky Pygmy Rattlesnake and the Saw-Scaled viper
Two frequently used drugs used to treat heart attacks in the United States come from snake venom. The first comes from the Dusky Pygmy Rattlesnake (Sistrurus miliarius barbourin). This little snake lives throughout the southern states of North America. It is common in Florida and its bite is not usually life threatening as it is much smaller than its more dangerous cousins. While not fatal, the venom of the snake is hemotoxic. Hematotoxins are toxins that destroy red blood cells, disrupt blood clotting and generalised tissue damage. Its venom contains a very unusual small protein (45–84 amino acids in length) called ‘disintegrin’ which has an important role in stopping blood platelets from aggregating and forming blood clots. This tiny protein stops blood clots by competitive inhibition of a receptor site that fibrinogen uses to adhere to platelets. The drug ‘Eptifibatide’ mimics the action of ‘disintegrin’ and it used as an anti-clotting agent to prevent thrombus formation. As many of us know once a thrombus forms it can embolise and be transported by the vascular system causing a stroke or heart attack or pulmonary oedema. Eptifibatide was approved by the FDA in 1998.
The second is ‘Tirofiban’ which is remarkably like Eptifibatide. Tirofiban was developed from the Saw-Scaled viper (Echis carinatus ) and approved in 1999. Tirofiban (trade name ‘Aggrastat’) is another anti-clotting protein that competitively inhibits the same cell receptor but there the similarities end. The Saw-Scaled viper, unlike Dusky Pygmy Rattlesnake, is one of India’s ‘Big Four’: the four species of snake that cause the most deaths annually. Public health specialists estimate that about 46,000 people die in India every year due to snake bites, a third of the world’s snakebite toll. Its bite generates such a complex medical issue that there are nine different antivenoms that target it. Perhaps not surprisingly, given the actions of tirofiban, the most serious symptoms of envenomation result from blood-clotting abnormalities and internal bleeding, which can lead to acute kidney failure.
Cardiovascular diseases are the leading cause of death worldwide as they account for nearly 18 million deaths yearly. In 2015 the most prescribed medicine in the UK were ACE inhibitors, such as ‘Lisinopril’ and ‘Ramapril’, followed by statins. ACE inhibitors were given to 15% of the adult population. Up to one in every 1,000 people are also affected by venous thrombosis and about 30% of those will develop further complications. Based on these statistics we can be thankful for what snakes have contorbuted!