From Bite to Breakthrough: Innovative Anticoagulant molecule from Blood-sucking organisms

 

Nature has provided blood-sucking organisms like leeches, ticks and mosquitos with interesting tools to secure their existence. When these animals bite, they inject saliva containing natural anticoagulants, which keep blood from clotting. Leeches, for example, produce hirudin, which particularly inhibits thrombin, a key enzyme in the blood coagulation process. This allows them to continue feeding on their host's blood uninterrupted. The study of these natural anticoagulants inspired the development of synthetic anticoagulants utilized in modern medicine. These drugs are crucial for preventing and treating illnesses like deep vein thrombosis, pulmonary embolism, and strokes. Commonly used anticoagulants, such as warfarin and heparin, pose severe hazards. Warfarin requires continual monitoring and dietary restrictions to avoid harmful interactions, whereas heparin, while effective, is derived from pig intestines and necessitates a vast farming infrastructure that emits pollution and greenhouse gases.

Thrombin, a vital enzyme in the coagulation cascade, transforms fibrinogen to fibrin, which forms the structural foundation of a blood clot. Inhibiting thrombin has been a key technique in anticoagulant therapy. However, typical thrombin inhibitors frequently lack selectivity, impacting other proteins in the coagulation pathway and increasing the risk of bleeding. The problem has been to develop a mechanism to selectively suppress thrombin without interfering with other functions in the body. Aptameric hirudins are a new class of anticoagulants that have been developed by researchers. These synthesized compounds were inspired by hirudin, a natural anticoagulant found in leech saliva. Aptameric hirudins are intended to target thrombin with great specificity, binding to both the exosite and active site of the enzyme. This dual targeting mechanism is known as EXosite-ACTive Site (EXACT) Inhibition.

 

Rational design of Thrombin – binding EXACT Inhibitor

One of the most striking characteristics of aptameric hirudins is their selectivity. These compounds effectively restrict thrombin activity by specifically attaching to its exosite and active site while not interfering with other coagulation cascade components. This lowers the chance of bleeding, which is a frequent and significant side effect of many anticoagulants. Additionally, aptameric hirudins are reversible inhibitors. In an emergency or when surgery is required, the anticoagulant effect can be rapidly reversed, lowering the risk of bleeding problems. The development of aptameric hirudins as EXACT inhibitors has great promise for improving thrombotic disease management. As research advances, aptameric hirudins may become a cornerstone of current anticoagulant therapy, showcasing the promise of novel biotechnological solutions to advance healthcare.

 

 

REFERENCES

1. Yu, Haixiang, Shekhar Kumar, James W. Frederiksen, Vladimir N. Kolyadko, George Pitoc, Juliana Layzer, Amy Yan et al. "Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors." Nature Communications 15, no. 1 (2024): 3977.

IMAGE SOURCE

1. Cover image: https://bpac.org.nz/2023/anticoagulants.aspx

2. Nature communications : https://www.nature.com/articles/s41467-024-48211-6#Abs1