Venoms in medicine

Last updated November 21, 2023

Venom in medicine is the medicinal use of venoms for therapeutic benefit in treating diseases.

Venom is any poisonous compound secreted by an animal intended to harm or disable another. When an organism produces a venom, its final form may contain hundreds of different bioactive elements that interact with each other inevitably producing its toxic effects.^[1] This mixture of ingredients includes various proteins, peptides, and non-peptidic small molecules.^[2] The active components of these venoms are isolated, purified, and screened in assays. These may be either phenotypic assays to identify component that may have desirable therapeutic properties (forward pharmacology) or target directed assays to identify their biological target and mechanism of action (reverse pharmacology).^[3]

Background

Venoms are naturally occurring substances that organisms evolved to deploy against other organisms, in defense or attack.^[2] They are often mixtures of proteins that act together or singly to attack their specific targets within the organism against which they are used, generally with high specificity and generally easily accessible through the vascular system.^[2] This has made venoms a subject of study for people who work in drug discovery.^[2] With developments in omic technologies (proteomics, genomics, etc.), researchers in this field became able to identify genes that produce certain elements in an animal's venom, as well as protein domains that have been used as building blocks across many species.^[2] In conjunction with methods of separation and purification of compounds, scientists are able to study each individual compound that exists within a venom "concoction", looking for compounds to serve as drug leads or other use.^[2] Each venomous organism produces thousands of different proteins giving access to millions of different molecules that still have potential uses. In addition, nature is continuously evolving; as prey develop resistance to these venoms, the predators also evolve as well, creating novel toxins that can continue to act upon its respective prey.^[4]

History

The earliest known use of venom in medicine dates back to 380 B.C. in ancient Greece.^[5] Aristotle's "Historia Animalium", describes how venom can be used in the production of antidotes for the venom.^[5] During the height of the Roman empire, there is evidence of venom being added into medicine used to treat smallpox, leprosy, fever, and wounds.^[5] Despite this, early uses of venom were primarily involved in the process of making antidotes. This use of venom continued into the Middle Ages and well into the 19th century. The first modern study of venom in a medical light occurred in the late 19th century. A scientist, Albert Calmatte, injected animals with small amounts of venom, using their blood as the antidote.^[5]

Marketed drugs

Captopril

Captopril emulates the function of the toxin found in Brazilian pit viper ( Bothrops jararaca ) venom and is generally accepted as the first venom "success" story. Captopril is an ACE inhibitor (angiotensin-converting enzyme) that was approved by the FDA approved in April 1981. It lowers blood pressure by inhibiting the production of angiotensin II which acts in a pathway that leads to vasoconstriction which raises blood pressure. After the creation of this drug, many analogues (enalapril, lisinopril, perindopril, ramipril, etc.) were produced.^[6]

Ziconotide

Ziconotide is a synthetically made version of the ω-conotoxin made by the cone snail,^[7] that is used to treat severe pain and is delivered as an infusion into the cerebrospinal fluid using an intrathecal pump system.^[8] Ziconitide acts presynaptically on N-type calcium channels, blocking the receptors of this channel with high selectivity and affinity,^[7]

Eptifibatide

Eptifibatide was modeled after a component in southeastern pygmy rattlesnake venom and is used in anticoagulation therapies in an effort to reduce the risk of heart attacks; it is used in only severe cases because of the possible side effect of thrombocytopenia, a condition where platelets are unable to aggregate at all.^[9]^[10]^[11] Eptifibatide binds reversibly to platelets reducing the risk of thrombosis. It is an antagonist of glycoprotein IIb/IIIa.^[9]

Exenatide

Exenatide is a 39-amino-acid peptide that is a synthetic version of exendin-4, a hormone found in the saliva of the Gila monster.^[12] It is used to treat Type II Diabetes as an adjunct to insulin and other drugs.^[13]^[14] It is GLP-1 receptor agonist that was first isolated by John Eng in 1992 while working at the Veterans Administration Medical Center in the Bronx, New York.^[12]

Batroxobin

Batroxobin, is a serine protease found in snake venom produced by Bothrops atrox and Bothrops moojeni , venomous species of pit viper found east of the Andes in South America. It cleaves fibrinogen, similarly to thrombin. Batroxobin from B atrox is used as a drug called "Reptilase" that is used to stop bleeding, while batroxobin from B moojeni is a drug called "Defibrase", used to break up blood clots. It is also used in a system called "Vivostat", where a person's blood is taken just before surgery and exposed to batroxobin; the resulting clots are then harvested, and then dissolved, forming a fibrin glue that is then used on the person during the surgery.^[15]

Related Research Articles

<span class="mw-page-title-main">Venom</span> Toxin secreted by an animal

Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved venom apparatus, such as fangs or a stinger, in a process called envenomation. Venom is often distinguished from poison, which is a toxin that is passively delivered by being ingested, inhaled, or absorbed through the skin, and toxungen, which is actively transferred to the external surface of another animal via a physical delivery mechanism.

Bradykinin (BK) (Greek brady-, slow; -kinin, kīn(eîn) to move) is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor and makes veins constrict, via prostaglandin F2, thereby leading to leakage into capillary beds, due to the increased pressure in the capillaries. Bradykinin consists of nine amino acids, and is a physiologically and pharmacologically active peptide of the kinin group of proteins.

Captopril, sold under the brand name Capoten among others, is an angiotensin-converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first oral ACE inhibitor found for the treatment of hypertension. It does not cause fatigue as associated with beta-blockers. Due to the adverse drug event of causing hyperkalemia, as seen with most ACE Inhibitors, the medication is usually paired with a diuretic.

Bothrops atrox — also known as the common lancehead, fer-de-lance, barba amarilla and mapepire balsain — is a highly venomous pit viper species found in the tropical lowlands of northern South America east of the Andes, as well as the Caribbean island of Trinidad. No subspecies are currently recognized.

Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are also able to spit venom.

A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical synthesis and have played a central role in the development of the field of organic chemistry by providing challenging synthetic targets. The term natural product has also been extended for commercial purposes to refer to cosmetics, dietary supplements, and foods produced from natural sources without added artificial ingredients.

Ziconotide, sold under the brand name Prialt, also called intrathecal ziconotide (ITZ) because of its administration route, is an atypical analgesic agent for the amelioration of severe and chronic pain. Derived from Conus magus, a cone snail, it is the synthetic form of an ω-conotoxin peptide. It is 1,000 times as powerful as morphine.

A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.

The Chinese red-headed centipede, also known as the Chinese red head, is a centipede from East Asia. It averages 20 cm (8 in) in length and lives in damp environments.

Tirofiban, sold under the brand name Aggrastat, is an antiplatelet medication. It belongs to a class of antiplatelets named glycoprotein IIb/IIIa inhibitors. Tirofiban is a small molecule inhibitor of the protein-protein interaction between fibrinogen and the platelet integrin receptor GP IIb/IIIa and is the first drug candidate whose origins can be traced to a pharmacophore-based virtual screening lead.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca²⁺ channels such as N-type and T-type channels.

Batroxobin, also known as reptilase, is a snake venom enzyme with Venombin A activity produced by Bothrops atrox and Bothrops moojeni, venomous species of pit viper found east of the Andes in South America. It is a hemotoxin which acts as a serine protease similarly to thrombin, and has been the subject of many medical studies as a replacement of thrombin. Different enzymes, isolated from different species of Bothrops, have been called batroxobin, but unless stated otherwise, this article covers the batroxobin produced by B. moojeni, as this is the most studied variety.

<span class="mw-page-title-main">Teprotide</span> Chemical compound

Teprotide is nonapeptide which has been isolated from the snake Bothrops jararaca. It is an angiotensin converting enzyme inhibitor (ACE inhibitor) which inhibits the conversion of angiotensin I to angiotensin II and may potentiate some of the pharmacological actions of bradykinin. It has a molecular formula of C₅₃H₇₆N₁₄O₁₂ and has been investigated as an antihypertension agent.

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

Atrolysin A is an enzyme that is one of six hemorrhagic toxins found in the venom of western diamondback rattlesnake. This endopeptidase has a length of 419 amino acid residues. The metalloproteinase disintegrin-like domain and the cysteine-rich domain of the enzyme are responsible for the enzyme's hemorrhagic effects on organisms via inhibition of platelet aggregation.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

Venom in snakes and some lizards is a form of saliva that has been modified into venom over its evolutionary history. In snakes, venom has evolved to kill or subdue prey, as well as to perform other diet-related functions. While snakes occasionally use their venom in self defense, this is not believed to have had a strong effect on venom evolution. The evolution of venom is thought to be responsible for the enormous expansion of snakes across the globe.

Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).

Three-finger proteins or three-finger protein domains are a protein superfamily consisting of small, roughly 60-80 amino acid residue protein domains with a common tertiary structure: three beta strand loops extended from a hydrophobic core stabilized by disulfide bonds. The family is named for the outstretched "fingers" of the three loops. Members of the family have no enzymatic activity, but are capable of forming protein-protein interactions with high specificity and affinity. The founding members of the family, also the best characterized by structure, are the three-finger toxins found in snake venom, which have a variety of pharmacological effects, most typically by disruption of cholinergic signaling. The family is also represented in non-toxic proteins, which have a wide taxonomic distribution; 3FP domains occur in the extracellular domains of some cell-surface receptors as well as in GPI-anchored and secreted globular proteins, usually involved in signaling.

Venomics is the large-scale study of proteins associated with venom. Venom is a toxic substance secreted by animals, which is typically injected either offensively or defensively into prey or aggressors, respectively.

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