Targeted protein degradation shows promise for Alzheimer's treatment

Breaking down modified proteins in the body could cure Alzheimer's disease.
Rupendra Brahambhatt
3d illustration of proteins.
3d illustration of proteins.

Christoph Burgstedt/iStock 

Scientists at Kyung Hee University (KHU) in South Korea have developed a peculiar protein-breaking compound that could bring us close to developing novel treatment methods for Alzheimer’s and various other diseases that currently have no cure.    

The compound is called PRZ-18002, and it can cause the degradation of p38, a protein associated with Alzheimer’s disease. Scientists in the past have also tried to break down p38 protein using drugs, but those methods weren’t efficient. They often missed the target protein, which further led to side effects. 

The researcher at KHU claims that so far, they didn’t notice any such problem with their targeted protein degradation (TPD) approach. They successfully tested PRZ-18002 in mouse models, and the compound delivered promising results.

Treating the untreatable 

Before we dig deep into how PRZ-18002 works, it is first important to understand why we need a protein degrader to cure some diseases. The researchers explain that some diseases like Alzheimer’s are caused due to posttranslational modification of proteins in the body. Such modifications alter the properties and amino acid configurations in a protein

The modified proteins then activate the pathways responsible for causing a disease. For instance, after going through posttranslational modification, the shape of the p38 protein changes because of the addition of a phosphate group. This addition triggers certain pathways in the body that lead to Alzheimer’s

Unfortunately, drugs and medications can not reverse this change because they are unable to interfere with the modified protein. The researchers, therefore, realized the only way to treat the diseases caused by modified proteins is to target and degrade the protein. 

During their study, they tested different chemicals against p38 and found that the compound PRZ-18002 successfully degraded and activated the modified version of p38. The researchers also used the compound against 96 other p38-like protein-modifying enzymes to check its selectivity. 

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Surprisingly, PRZ-18002 was able to identify what it should target and what it should not.

To confirm these findings, they further tested the compound on mice with Alzheimer’s disease. Interestingly, the study authors noticed improvements in the spatial reasoning and cognitive abilities of mice. The p38 activity also got suppressed after the use of PRZ-18002, bringing positive changes in the overall chemistry of mice brains.  

The results of this experiment suggest that PRZ-18002 has the potential to provide us with novel and effective treatment methods for curing Alzheimer’s and various other diseases caused by modified proteins. 

The study is published in the journal ACS Central Science.

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