Acetaminophen poisoning? New synthetic oligosaccharides to help

Acetaminophen is widely used as antipyretic, analgesic and cold medicine because of its good analgesic effect and no addiction. For example, the familiar Xin Kang Taike, Tylenol, Gan Kang, white and black, etc. It is generally believed that acetaminophen is safe to take at normal doses for both children and adults. However, studies have shown that long-term and overdose of acetaminophen may cause adverse consequences. In the United States, about 50% of drug-induced liver injury is caused by overdose of acetaminophen. About 80,000 people are caused by acetaminophen each year. Poisoned and admitted to hospital.
 
The main mechanism of acetaminophen causing liver damage is that its metabolite N-acetyl-4-benzoquinoneimine (NAPQI) binds to glutathione in the liver, which leads to its inactivation, and excessive consumption of glutathione Liver cell necrosis, and then release HMGB1, which further interacts with the receptor for advanced glycation end products (RAGE) on the surface of neutrophils to attract neutrophils, leading to inflammatory cell infiltration and activation of sterile inflammatory processes, and ultimately leading to liver The damage continues to be amplified and exacerbated. This mechanism of action is also known as the HMGB1/RAGE axis.
    
At present, the standard treatment drug for acetaminophen poisoning in clinical practice is acetylcysteine, which mainly acts by neutralizing the metabolite of acetaminophen, NAPQI. Therefore, it must be administered early and must be taken before overdose of acetaminophen 8 The medication is effective within hours, which leads to a shorter medication window. Therefore, a high-efficiency drug with a longer action window becomes an urgent need to treat this type of liver injury.

On March 18, 2020, Science Translational Medicine published a study titled "Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure", reporting a new type of chemical enzymatic synthesis of heparan sulfate Stearyl sugar can effectively treat acute liver injury caused by acetaminophen overdose. Compared with the standard drug acetylcysteine that neutralizes NAPQI, the target of this new heparan sulfate oligosaccharide is HMGB1/RAGE. Axis, by neutralizing HMGB1 to inhibit its binding to RAGE and induce neutrophil aggregation. In the course of the disease, the infiltration of neutrophils caused by HMGB1 is later than the production of NAPQI and the process of causing hepatocyte necrosis. Therefore, the medication window period is significantly wider than that of acetylcysteine, which provides the treatment of this type of acute liver injury. New treatment options and approaches.

Since the heparin incident in 2008, the shortcomings of heparin extracted from animal tissues such as easy contamination and large differences between batches have been exposed. Everyone has begun to turn their attention to synthetic heparin drugs with a clear and uniform structure, and further expand to Heparan sulfate oligosaccharide drugs. Synthetic heparin and heparan sulfate carbohydrate drugs have the characteristics of uniform structure and relatively clear targets. By precisely controlling the sulfate modification at different positions, they can have completely different effects.

For example, in the article, the author compared two different stearyl sugars 18mer-HP and 18mer-AXa, both of which have exactly the same monosaccharide structure. Compared with the former, 18mer-AXa is mainly modified by the 6-position substituent. And this subtle structural difference causes 18mer-HP to treat acute liver injury without anticoagulant effect, 18mer-AXa shows good anticoagulant effect but not liver protection.

Heparan sulfate is widely present on the surface of all mammalian cells and interacts with a variety of important proteins. Therefore, drugs that target the interaction of heparan sulfate with proteins can essentially block signal transduction more effectively and apply widely. The potential efficacy of heparan sulfate stearyl sugar in the treatment of liver injury has brought more confidence to researchers and believes that synthetic oligosaccharide drugs will have more extensive applications and prospects in the future.