Exploring the scientific quest to find inhibitors for snake venom myotoxins using functional, structural and bioinformatics approaches
Snakebite envenoming represents a devastating public health crisis disproportionately affecting rural populations in tropical regions. The World Health Organization classifies it as a neglected tropical disease of high priority, with approximately 100,000 deaths annually and about three times as many amputations and permanent disabilities worldwide 1 .
Annual fatalities from snakebites
Annual amputations and permanent injuries
Most affected region with Bothrops genus
At the heart of this local tissue destruction are specialized proteins known as phospholipase A2-like (PLA2-like) toxins, which are abundant in viper venoms 1 .
These toxins resemble enzymatically active phospholipases structurally but have evolved to cause muscle damage through different mechanisms 1 .
A well-studied PLA2-like toxin from Bothrops moojeni with unique structural differences that make it particularly efficient at causing muscle damage 1 .
The toxin binds to hydrophobic molecules at its hydrophobic channel, causing activation and stabilization 1 .
The activated toxin interacts with muscle cell membranes at specific membrane-docking sites (MDoS) 1 .
Through the membrane-disrupting site (MDiS), the toxin damages cell membranes, leading to cell death 1 .
A groundbreaking study tested two candidate inhibitors against the destructive MjTX-II toxin: acetylsalicylic acid (ASA)—the common aspirin—and rosmarinic acid (RA)—a polyphenolic compound found in plants 1 .
87.3% prevention of muscle paralysis
Binds near membrane-disrupting site
Remains tightly bound in simulations
No significant protection against paralysis
Binds to hydrophobic channel
Tends to dissociate quickly
The search for effective toxin inhibitors relies on sophisticated research tools that span functional, structural, and computational approaches 1 2 .
| Research Tool | Primary Function | Key Insights Generated |
|---|---|---|
| Myographic Assays | Measure muscle contraction strength | Quantifies protective effects of inhibitors |
| X-ray Crystallography | Determines atomic-level 3D structures | Reveals precise binding locations |
| Molecular Dynamics Simulations | Models molecular movements over time | Predicts binding stability |
| Cellular Thermal Shift Assay (CETSA) | Validates drug-target engagement | Confirms physiological relevance |
The structural insights gained from these studies are guiding the design of more effective inhibitors 1 .
RA binds near the membrane-disrupting site, directly interfering with toxin function 1 .
RA distorts dimeric assembly, affecting toxin orientation and stabilization 1 .
Effective inhibition may require targeting different regions and mechanisms .
| Inhibitor | Source | Binding Site | Mechanism of Inhibition |
|---|---|---|---|
| Rosmarinic Acid | Plants | Near membrane-disrupting site | Blocks membrane interaction, distorts structure |
| Suramin | Synthetic compound | Varies between toxins | Interferes with protein oligomerization |
| Fatty Acids | Natural metabolites | Hydrophobic channel | Prevents toxin activation |
The compelling research on rosmarinic acid and other small molecule inhibitors offers hope for addressing the critical gap in snakebite treatment 1 .
The discovery that plant-derived compounds can effectively neutralize myotoxins validates investigating traditional medicinal plants used in folk medicine for snakebite treatment 1 .
Each structural insight and functional validation brings us closer to effective complementary treatments that could prevent the lifelong disabilities that all too often result from snakebite.