Animal Venoms: The Healing Bite

2. November 2016
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Animal venoms are supposed to deter, incapacitate or kill adversaries. Increasingly however, researchers keep discovering that the venom of snakes, scorpions or spiders can also cure diseases, and that this is even lucrative. Captopril and the antidiabetic exenatide have led the way.

Worldwide, there are more than 100,000 venomous animals. Each individual venom is constituted from a combination of up to 500 toxins. These specifically bind to certain receptors, for example in the heart or nervous system, and can kill their prey within minutes. However, the toxins can do even more: in low doses, individual components of the venoms act as an antidiabetic or against high blood pressure and cancer.

They frequently bind to key molecules in human cells and alter the physiological processes which have been disrupted by the disease. Patients with intractable pain or other neurological complaints need medications, for example, which inhibit the firing of neurons. This is accomplished via neurotoxic snake and spider venoms. By way of small variations in chemical composition or through adjusted dosage, the toxin is converted into a pharmaceutical. This process of examining living organisms in particular with a view toward pharmaceutical aims, and the subsequent chemical modifications involved, are called bioprospecting.

Using venom against hypertension

About half a dozen drugs derived from snake venom have been developed and approved. One of the first was captopril. This ACE inhibitor blocks the angiotensin converting enzyme in the renin-angiotensin-aldosterone-system. It lowers blood pressure, helps with heart failure and reduces the risk of heart attack and stroke. The template for development was the peptide BPP5a (bradykinin potentiating peptide) which is present in the venom of the jararaca pit viper (Bothrops jararaca), a Brazilian snake. BPP5a itself was not suitable as a drug because it is rapidly degraded. Through some modifications, scientists were able to prolong its effect. It was already developed as a antihypertensive in the 1970s. Since its introduction in 1981, captopril has probably saved more people’s lives than the number of those who have died from the poison of the jararaca pit-viper and other vipers in the last centuries. The success of the high blood pressure medicine paved the way for further bioprospecting.

Diabetes agent from monster saliva

The Gila monster (Heloderma suspectum), lives in the drylands of south-western North America. Although it is very cumbersome, it can bite quickly. Its venom is not injected via hollow teeth as in snakes but rather massaged in by chewing. Within the administered poison cocktail, among other substances, is a polypeptide with the name exendin-4. This molecule was discovered in the early 1990s by the New York endocrinologist John Eng. He also developed a synthetic version of the substance exenatide, and sold it to the company Amylin.

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The poisonous Gila monster can grow up to 50 cm long; source: Biodiversity Heritage Library flickr.de

Exenatide was the first drug from the incretin mimetic class. Substances in this class mimic the endogenous incretin glucagon-like peptide-1 (GLP-1) formed in the intestine. GLP-1 is released from the gut after eating. It binds to the GLP-1 receptor and stimulates the release of insulin from the beta cells. In addition, GLP-1 lowers the glucagon levels, delays gastric emptying and inhibits hunger and thirst.

The use of the body’s own incretin as an active agent is not suitable, since it is degraded within a few minutes by the enzyme dipeptidyl peptidase-4(DPP-4). The synthetic hormone exenatide in contrast is active for hours. Another advantage is that it – unlike insulin injections – acts independently of glucose. It releases insulin only when blood sugar is high, whereby unintentional hypoglycaemia is able to be prevented. Exendin-4 however acts not only on the pancreas, but stimulates the growth of neurons and prevents mature neurons from dying.

Thus in 2012 scientists at the National Institute On Aging, United States, began support for a clinical study on the effect of exendin-4 on people suffering Alzheimer at an early stage, or suffering from a mild cognitive impairment.

The success of exenatide sparked a genuine competition among drug manufacturers. In Germany for example liraglutide, developed by Novo Nordisk, was approved in 2009. In the first year alone the drug brought the company more than one billion dollars. Two years later, a new formulation of the antidiabetic exenatide was authorised under the name of Bydureon.

Exenatide is as part of this formulation encapsulated in microspheres comprised from a biodegradable polymer. The drug only has to be injected subcutaneously once a week instead of once a day. Nevertheless, the common challenge also applies to these medications: no remedial impact without associated side effects. In 2013, the FDA made it known that incretin mimetics can increase the risk of pancreatitis and promote precancerous cell changes.

Scorpion venom in phase I

In addition to high blood pressure and diabetes, venoms can also be used in cancer therapy. The substance named BLZ-100 for example consists of an optide and the fluorescent dye indocyanine green. The term “optide” stands for optimised peptide. In the case of BLZ-100, the active substance chlorotoxin was optimised. This small peptide is composed of 36 amino acids and was discovered in the venom of the most poisonous scorpions in the world, the Yellow Mediterranean Scorpion (Leirus quinquestriatus).

BLZ-100 specifically inhibits certain voltage-dependent chloride ion channels which occur at amplified levels in cancer cells such as gliomas, melanomas, neuroblastomas or medulloblastomas. These are required in order to control, among other things, excitability and homeostasis, and in maintaining the acid-base balance. They are also important in the immune response to, proliferation, differentiation of, invasion by and migration of the cancer cells. The cancer cells with BLZ-100 are then visible to the doctor because of the dye. In this way tumours can be better found and removed. Starting last year, BLZ-100 has been and is being tested on children and young adults with brain and skin tumours as part of a phase I study.

Anemone, spiders and centipedes with potential

Yet it’s not only snakes or scorpions which come into the picture as active agent sources, but so to do sea anemones. The active ingredient dalazatide, formerly ShK-186, mimics a peptide which was isolated from the venom of the Caribbean Sea Anemone (Stichodactyla helianthus).

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The venom of Sea Anemone contains an interesting pharmaceutical agent for multiple sclerosis; source: James St. John, flickr.de

Dalazatide does not suppress the complete immune system but only blocks the effector memory T-cells – a subset of the T cells, the cause of many autoimmune diseases. The substance has been tested in a phase I B study of 24 psoriasis patients.

And that’s not all: a protein found in the venom of tarantula could be used for the treatment of muscular dystrophy, pain could be ameliorated using a component of the centipede venom and erectile dysfunction treated by using a toxin from the Brazilian wandering spider (Phoneutria nigriventer) [Paywall]. Bee venom – last but not least – works even better on crow’s feet than Botox, if one is permitted to believe South Korean biologists and Elle Magazine.

Book publication:

Venomous: How Earth’s Deadliest Creatures Mastered Biochemistry
Wilcox, C; Scientific American / Farrar, Straus and Giroux, ISBN 10: 0374283370, ISBN 13: 9780374283377 ; 2016

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2 comments:

Marc Van Wijk
Marc Van Wijk

Homeopathy is using venoms for centuries… with great succes!

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Barry Wilbourn
Barry Wilbourn

Excellent article. The Jararaca pit viper venom also contains another component called botrocetin which increases the affinity of the von Willebrand factor A1 domain for its platelet receptor complex Gp1b alpha (CD42b) thereby causing platelet activation.

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