TAG: GS 3: SCIENCE AND TECHNOLOGY
THE CONTEXT: A consortium of scientists, funded by the Wellcome Trust, embarked on a revolutionary approach to antivenom development, bypassing animal-derived antibodies and instead harnessing human antibodies.
EXPLANATION:
- Led by Kartik Sunagar from the Indian Institute of Science, Bengaluru, the team focused on synthesizing broadly applicable human antibodies against snake venom toxins.
- Snakebites, though often considered exotic, pose a significant threat to millions of people worldwide, particularly in low and middle-income countries such as India and Africa.
- With more than 100,000 fatalities annually and around 400,000 individuals left permanently disabled, snakebites represent a critical yet neglected health crisis.
- The burden is especially pronounced in regions where access to proper healthcare is limited, exacerbating the mortality rate.
- Traditional methods of producing antivenom involve injecting large animals like horses with snake venom and harvesting the antibodies produced in their blood.
- However, this process has inherent limitations.
- The antibodies obtained from animals may target other microorganisms and non-harmful components of the venom, resulting in variability and the need for larger doses.
- Moreover, using animal-derived antibodies increases the risk of adverse reactions in humans.
Targeting Three-Finger Toxins (3FTxs)
- The scientists honed in on three-finger toxins (3FTxs), a prevalent and lethal component found in elapid venoms, which include species like cobras, kraits, and mambas.
- Specifically, they targeted α-neurotoxins, a class of 3FTxs that disrupt human nerve and muscle cell receptors, leading to paralysis and eventual death.
Innovative Screening Process
- Utilizing advanced techniques, the researchers screened billions of human antibodies expressed on yeast cells to identify those that bound most effectively to the targeted toxins.
- This method allowed them to select antibodies with unprecedented precision, surpassing the capabilities of traditional animal-based approaches.
Identification of 95Mat5: A Potent Antidote
- After rigorous screening, the team identified an antibody, 95Mat5, which demonstrated remarkable efficacy in neutralizing a wide range of snake venoms, including those from cobras, kraits, and mambas.
- In in vitro experiments conducted by Nicholas Casewell’s group at the Liverpool School for Tropical Medicine, 95Mat5 showed promising results in neutralizing toxins in human cells.
In Vivo Validation
- Further validation in live mice confirmed the efficacy of 95Mat5 in protecting against lethal doses of snake venom.
- Notably, the antibody provided significant protection against various elapid venoms, with the exception of king cobras, where it only delayed death.
Unprecedented Success and Future Prospects
- The success of 95Mat5 marks a significant advancement in antivenom development, offering a potential solution to the complex challenge of snakebite envenoming.
- By targeting a specific toxin present in multiple snake venoms, this antibody represents a crucial step towards a universal antivenom.
Towards a Universal Antivenom
- While 95Mat5 effectively neutralizes a specific toxin, the quest for a universal antivenom continues.
- Sunagar and his team express optimism in discovering additional antibodies targeting toxins in other snake venoms, such as vipers.
- This pursuit holds the promise of a comprehensive solution to snakebite envenoming, transcending geographical and species-specific barriers.
Three-Finger Toxins (3FTxs):
- Three-finger toxins (3FTx) are a superfamily of small toxin proteins found in the venom of snakes, primarily from the Caenophidia lineage.
- They are named after their characteristic structure, which consists of three beta strand loops (fingers) projecting from a small hydrophobic core containing four conserved disulfide bonds.
- The proteins are typically 60-74 amino acid residues long, and despite their conserved structure, they have a wide range of pharmacological effects, with most members being neurotoxins that act on cholinergic intercellular signaling.
- Three-finger toxins are divided into three classes: short-chain toxins, long-chain toxins, and three-finger protein domains.
- Short-chain toxins have under 66 residues and four core disulfide bonds, while long-chain toxins have at least 66 residues, a disulfide bond in loop II, and possibly a C-terminal extension.
- Three-finger protein domains, on the other hand, are non-toxic proteins that share a similar structure with three-finger toxins but have different functions.