December 5, 2023

Alzheimer’s and Other “Undruggable” Diseases Could Be Treated With Degraded Modified Proteins

Like lots of proteins, p38 goes through posttranslational adjustments, consisting of phosphorylation, to form p-p38. Nam-Jung Kim, Kyung-Soo Inn, Jong Kil Lee, and coworkers desired, for the first time, to produce a protein degrader that could target and break down p-p38, and potentially use a brand-new opportunity for treating Alzheimers disease.
The group evaluated several compounds specific for p-p38, eventually finding PRZ-18002, which selectively induced deterioration of p-p38 over both similar proteins and its inactivated form. PRZ-18002 preserved its selectivity even when checked against 96 different protein kinases similar to p38. When delivered to the brains of mouse designs of Alzheimers illness, the substance downregulated the p38 pathway, improving cognitive abilities, consisting of spatial thinking, and disease-related brain chemistry, such as the accumulation of amyloid-beta plaques.
The scientists state that this work could one day supply a novel treatment for Alzheimers disease and open up chances for future treatments of other illness that also involve customized proteins.
Recommendation: “Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimers Disease” 1 March 2023, ACS Central Science.DOI: 10.1021/ acscentsci.2 c01369.
The authors acknowledge funding from the National Research Foundation of the federal government of Korea (MSIT) and the Basic Research Laboratory Program and Medical Research Center Program of the National Research Foundation moneyed by the Korean Ministry of Science, ICT, and Future.

Scientists have created a substance that breaks and targets down a specific protein linked to Alzheimers, utilizing a strategy that directly targets and breaks apart proteins instead of simply interfering with them.
Specific illness, consisting of Alzheimers, are presently considered “undruggable” due to the fact that traditional small-molecule drugs cant interfere with the proteins responsible for the diseases. Scientists have actually been checking out targeted protein degradation (TPD) as a way to get at hard-to-treat proteins, namely, the ones for which inhibitors or other conventional strategies fail. Nam-Jung Kim, Kyung-Soo Inn, Jong Kil Lee, and associates wanted, for the first time, to develop a protein degrader that might break and target down p-p38, and possibly provide a brand-new opportunity for dealing with Alzheimers disease.

A new method has been established that might use a pathway towards treating particular “undruggable” diseases like Alzheimers. Currently, small-molecule drugs are unable to interfere with the proteins responsible for these diseases. Scientists have designed a compound that targets and breaks down a specific protein linked to Alzheimers, using a technique that straight targets and breaks apart proteins rather of just interfering with them.
Particular diseases, consisting of Alzheimers, are presently considered “undruggable” since standard small-molecule drugs cant hinder the proteins accountable for the health problems. A new method that specifically targets and breaks apart specific proteins– rather than just interfering with them– may provide a path towards treatment. Researchers reporting in ACS Central Science have, for the very first time, developed a substance that breaks and targets down a posttranslationally customized protein closely connected with Alzheimers illness.
Scientists have been exploring targeted protein destruction (TPD) as a method to get at hard-to-treat proteins, particularly, the ones for which inhibitors or other conventional methods fail. These degraders have shown some initial promise, things can get made complex if the proteins go through “post-processing,” or posttranslational modifications, after being formed. Hence far, no TPD method has been able to target this kind of protein.
One protein that would be especially advantageous to break down is p38, which is involved in several cellular signaling paths and is connected to the development of Alzheimers disease. Although previous attempts to treat the illness by focusing on p38 have actually been made– including a drug candidate that went through 2 phases of medical trials– they experienced off-target effects and minimal effectiveness.