TPD Show Potential For The Treatment of Alzheimer's Disease

By: Hunan Huateng Pharmaceutical Co. Ltd.
 
CHANGSHA, China - March 21, 2023 - PRLog -- In recent years, targeted protein degradation (TPD) technology has developed rapidly, especially proteolysis targeting chimera (PROTAC), which is the most representative technology of TPD strategy. TPD drugs are one of the hot spots of new drug development in recent years, especially in the field of oncology. For example, a TPD drug developed by Arvinas has achieved proof-of-concept in clinical trials for the treatment of breast and prostate cancer. Researchers are also developing TPD drugs to treat other types of diseases.

TPD developed based on this technique degrades p-p38 protein. Post-translational modification (PTM) of p38 protein into phosphorylated p-p38 is associated with the occurrence and development of AD. In mouse models of Alzheimer's disease, it improved cognition and reduced the accumulation of amyloid plaques. The study was published in the journal ACS Central Science.

At present, the research on TPD has made preliminary progress, but no technology can target the protein undergoing PTM. Proteins that undergo further processing become complex, but if a TPD tool could identify proteins with specific PTMs, it might provide a way to target abnormal PTMs to cause disease.

p38 is a key protein in the human body, participates in various signaling pathways, and is related to the occurrence and development of AD. There have been various attempts to target p38 to treat AD, but clinical trials of such drugs have shown off-target effects and limited therapies. Phosphorylated p38 structural changes, functional activation. By tracking this protein it may be possible to improve the specificity of treatment. Therefore, researchers first tried to develop TPD targeting p-p38, trying to provide new ideas for the treatment of AD.

After screening a variety of compounds specific to p-p38, the team finally identified PRZ-18002 as a candidate compound, which can selectively induce p-p38 degradation without interfering with similar proteins and unphosphorylated p38 .

In mouse models, PRZ-18002 treated AD mice showed selective degradation of p-p38 and downregulation of pro-inflammatory signaling pathways, alleviating AD-related neuroinflammatory and pathophysiological features such as cognitive impairment and Aβ protein accumulation.

"The TPD technique has advantages over gene knockout because it can induce selective degradation of disease-associated proteins due to pathological mutations or abnormal PTMS," the team said. This study demonstrates the tremendous potential of TPD as a novel therapeutic model in drug discovery. It has the potential to provide new treatments for Alzheimer's disease."

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