Venomous snakes are among the most well-known sources of venom, with over 3,600 species classified into 27 families worldwide. Snake venom is a complex mixture containing various enzymes like proteases, phospholipases, and nucleases, as well as non-enzymatic proteins and peptides that can have neurotoxic, hemotoxic, cytotoxic, and myotoxic effects. Despite its toxicity, snake venom has been used in traditional medicine for centuries, and its components are now being investigated as potential therapeutic agents for conditions like cancer, hypertension, and thrombosis.
Several FDA-approved drugs, such as the antihypertensive Captopril and antiplatelet agents Aggrastat and Integrilin, have already been developed based on snake venom components. Additionally, many other snake venom-derived compounds are currently in preclinical or clinical trials for various therapeutic applications, including the treatment of chronic pain, pulmonary embolism, and myocardial infarction.
The Chemical Composition of Snake Venom
Enzymatic and Non-Enzymatic Components
Snake venoms are complex mixtures of enzymatic and non-enzymatic components with specific pathophysiological functions, used as defense mechanisms or to immobilize and digest prey. They contain a wide variety of enzymes, including proteases, phospholipases, L-amino acid oxidases, and nucleases, as well as non-enzymatic proteins and peptides that target ion channels, membrane receptors, and components of the hemostatic system. These components can have neurotoxic, hemotoxic, cytotoxic, and myotoxic effects, and can also exhibit antimicrobial properties against bacteria, viruses, fungi, and parasites.
Diverse Protein Families
Snake venom is composed of a variety of molecules, including carbohydrates, nucleosides, amino acids, lipids, proteins, and peptides, with proteins and peptides being the major constituents. Over 30 different protein families have been identified in snake venom, and the composition varies widely between snake species and even within the same species.
- Enzymatic Proteins: Proteolytic enzymes, arginine ester hydrolases, hyaluronidases, phospholipases A2, acetylcholinesterase, nucleases, and L-amino-acid oxidases.
- Non-Enzymatic Proteins and Peptides: Cysteine-rich secretory proteins, snaclecs, proteinase inhibitors, nerve growth factors, bradykinin-potentiating peptides, natriuretic peptides, and three-finger toxins.
Peptide Families and Their Functions
Snake venom peptides can be classified into several families based on their structure and function, including:
- Three-Finger Toxins (3FTxs): Neurotoxins, cardiotoxins, acetylcholinesterase inhibitors, ion channel blockers/modulators, and platelet aggregation inhibitors.
- Kunitz-Type Serine Protease Inhibitors: Inhibit serine proteases like plasmin, kallikrein, and trypsin, and some also act as potassium and calcium channel blockers.
- Disintegrins: Bind to integrins and inhibit platelet aggregation, classified based on the presence of RGD, MLD or R/KTS motifs, with potential applications in treating cancer, asthma, diabetes, and neurodegenerative diseases.
- Natriuretic Peptides (NPs): Similar to mammalian NPs in structure and function, producing hypotensive effects and regulating cardiovascular and renal functions. Chimeric NPs like Cenderitide are being developed for clinical applications.
Chemistry of the Major Enzymatic Toxins
Major Enzymatic Toxin Families
The main enzymatic toxin families in snake venom are secreted phospholipases A2 (PLA2s), snake venom metalloproteinases (SVMPs), and snake venom serine proteases (SVSPs).
Secreted Phospholipases A2 (PLA2s)
- Catalyze the hydrolysis of phospholipids in cell membranes.
- Lead to myotoxicity and neurotoxicity.
Snake Venom Metalloproteinases (SVMPs)
- Degrade components of the extracellular matrix and blood coagulation factors.
- Cause hemorrhage.
Snake Venom Serine Proteases (SVSPs)
- Interfere with blood coagulation, blood pressure, and platelet aggregation.
Pathophysiological Effects
Snake venom components can have various pathophysiological effects, including:
- Neurotoxicity
- Hemotoxicity
- Cytotoxicity
- Myotoxicity
- Antimicrobial activity
These diverse effects are attributed to the complex mixture of enzymatic and non-enzymatic components present in snake venom, which serve as defense mechanisms or aid in immobilizing and digesting prey.
Snake Venom-Derived Drugs
Despite their toxicity, snake venom components have been used in traditional medicine for thousands of years and have become valuable sources for drug discovery, with several FDA-approved drugs based on snake venom components. Many other snake venom-derived compounds are currently in preclinical or clinical trials for various therapeutic applications, demonstrating the potential of snake venoms as a source of new drugs.
Approved Drugs and Therapeutic Applications
Several FDA-approved drugs have been developed based on snake venom components, including:
- Captopril and Enalapril: Antihypertensive drugs derived from bradykinin-potentiating factors in the venom of the jararaca pit viper that inhibit angiotensin-converting enzyme (ACE).
- Tirofiban and Eptifibatide: Antiplatelet drugs derived from disintegrins in saw-scaled viper and Barbour’s pygmy rattlesnake venom, respectively, that bind to the αIIBβ3 integrin.
- Defibrase/Reptilase: Used for treating thrombotic disorders.
- Exanta: Used for treating atrial fibrillation.
Additionally, snake venom components have shown potential for cancer therapy through mechanisms like antiangiogenesis and apoptosis induction. Future directions for research include isolating and characterizing new active molecules from snake venoms and developing new drug delivery systems by conjugating snake venom components with monoclonal antibodies or nanoparticles for targeted cancer therapy.
Other Applications
- Diagnostic Tools: Batroxobin, RVV-V, RVV-X, ecarin, botrocetin, and protac are used as diagnostic tools for coagulation disorders and antiphospholipid syndrome.
- Cosmetic Applications: Bee venom, argiotoxin-636, and synthetic tripeptide SYN®-AKE have cosmetic applications like anti-wrinkle and skin whitening effects.
- Alternative Therapies: Bee venom therapy and leech therapy (hirudotherapy) are used to treat conditions like pain, arthritis, multiple sclerosis, etc.
Challenges and Strategies
Key Challenges
Diversity and Complexity: The diversity of bioactive compounds in snake venom provides a rich source for drug discovery, but challenges remain in realizing the full therapeutic potential.
Antivenom Supply and Quality: In sub-Saharan Africa (SSA), there is only one antivenom (AV) producer based in South Africa, and most AV supplies are imported, placing African countries at supply risks.
- Many AV products imported into SSA have not been properly assessed and had suboptimal quality, leading to an unacceptable rise in mortality when used.
Affordability and Access: The cost of AV affects health budgets and individual out-of-pocket expenditure, making affordability a challenge for patients and health systems.
- Deployment of AV is through a ‘pull’ rather than ‘push’ system, leading to gross underserving of endemic rural areas.
Drug Development Challenges:
- The development of toxin-based drugs faces challenges, including the lengthy and costly preclinical and clinical studies required to validate their safety and efficacy.
- Challenges in drug development from animal venoms include sourcing high-quality samples, poor screening tests, and difficulties in purification and characterization.
Strategies and Solutions
WHO Roadmap and Financing:
- The WHO Roadmap aims to halve the snakebite burden by 2030, which would require an estimated 279,485 AV therapies annually at a cost of $51.43 to $66.24 million.
- Sustainable financing through increased budgetary allocation by SSA countries, as well as regional and international cooperation, will be critical to achieving the WHO Roadmap targets.
Improving Antivenom Programs:
- Strategies recommended include improving efficiencies of existing AV programs, exploring local AV production through public-private partnerships, and facilitating next-generation therapies like monoclonal antibodies.
Continued Research and Development:
- Despite the difficulties, animal venom research is warranted to discover new effective and selective drug and research molecules.
- Overcoming challenges in sourcing, screening, purification, and characterization is crucial for realizing the full therapeutic potential of snake venom-derived compounds.
Applications and Future Prospects
Potential for New Drug Development
Snake venom represents a rich source of bioactive compounds with potential for developing new drugs, especially in the cardiovascular and neurological domains. However, the diversity and variability of venom composition pose challenges for drug development. Non-snake venom compounds being developed include exenatide and lixisenatide from lizard venom for diabetes, bivalirudin and desirudin from leech venom for anticoagulation, and compounds from toad, frog, and bee venoms for cancer and pain.
Research Tools
Snake venom components are also important research tools, such as α-Bungarotoxin and α-Conotoxins for studying nicotinic acetylcholine receptors. These compounds serve as valuable probes for investigating various physiological processes and molecular targets, aiding in the development of new therapeutic strategies.
Future Prospects
- Continued exploration of snake venom components and their mechanisms of action could lead to the discovery of novel drug candidates for various therapeutic areas.
- Advancements in purification techniques, screening methods, and characterization tools may facilitate the identification and development of new snake venom-derived drugs.
- Combining snake venom components with targeted delivery systems, such as nanoparticles or monoclonal antibodies, could enhance their specificity and efficacy while minimizing potential side effects.
Conclusion
The article has provided a comprehensive overview of snake venom and its potential applications in modern medicine. While snake venom is known for its toxicity, it has been used in traditional medicine for centuries, and its components are now being explored as potential therapeutic agents for various conditions.
Snake venom is a complex mixture containing a diverse array of enzymatic and non-enzymatic components, each with unique pathophysiological functions. Despite the challenges associated with the development of venom-derived drugs, several FDA-approved drugs, such as Captopril and Tirofiban, have already been developed based on snake venom components. Additionally, many other venom-derived compounds are currently in preclinical or clinical trials for various therapeutic applications, demonstrating the immense potential of snake venom as a source of new drugs.
As research continues to unravel the mysteries of snake venom, it is essential to approach this field with empathy, understanding the challenges faced by those affected by snakebites and the need for accessible and affordable treatments. Collaboration and problem-solving are key to overcoming obstacles, such as improving antivenom supply and quality, ensuring affordability and access, and addressing the complexities of drug development from animal venoms. With a human touch and a commitment to finding innovative solutions, the potential of snake venom in modern medicine can be fully realized, ultimately benefiting patients and advancing healthcare worldwide.
FAQs
1. How is snake venom utilized in medical treatments?
Since the 1930s, cobra venom has been employed in the medical field to address conditions such as asthma, polio, multiple sclerosis, rheumatism, severe pain, and trigeminal neuralgia. Components derived from snake venom, such as L-amino acid oxidase (LAAO) and phospholipase A2 (PLA2), have been identified for their antimicrobial properties.
2. What are the current medical procedures for treating a snake bite?
In the event of a snake bite, treatment at an emergency department typically includes the administration of antibiotics to prevent or treat infections, pain-relieving medications, and antivenin. The specific antivenin used depends on the snake species involved and the severity of the symptoms.
3. Is there an effective treatment available for snake venom poisoning?
The primary treatment for severe snake envenomation is antivenom. Administering antivenom promptly is crucial to halt the irreversible damage caused by the venom.
4. What historical and medicinal benefits are associated with venom?
Historically, venom has been incorporated into treatments for diseases like smallpox, leprosy, fever, and wounds during the Roman Empire era. Although venom’s primary role was in antidote development, its medicinal use persisted through the Middle Ages and into the 19th century.
References
[1] – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832721/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832721/
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[3] – https://www.nature.com/articles/s41570-022-00393-7 https://www.nature.com/articles/s41570-022-00393-7
[4] – https://www.news-medical.net/health/The-Medical-Uses-of-Venom.aspx https://www.news-medical.net/health/The-Medical-Uses-of-Venom.aspx
[5] – https://www.intechopen.com/chapters/81270 https://www.intechopen.com/chapters/81270
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