Certain disorders, including Alzheimer’s, are currently considered “undruggable” because traditional small molecules can’t interfere with the disease-associated proteins that are responsible. Researchers headed by a team at Kyung Hee University suggest that a new technique developed to specifically target and break apart pathogenic post-translationally modified proteins may offer a new approach to treatment. Using the targeted protein degradation (TPD) technology the team designed a compound that specifically breaks down a form of a protein called p38, which is undergoes post-translational modification (PTM) into a phosphorylated p-p38, that is linked with Alzheimer’s disease (AD).

The researchers describe their work, including initial results from experiments in mouse models of AD, in ACS Central Science, in a paper titled “Chemical Knockdown of Phosphorylated p38 Mitogen-Activated Protein Kinase (MAPK) as a Novel Approach for the Treatment of Alzheimer′s Disease.” In their report, co-corresponding author Jong Kil Lee, PhD, and colleagues, concluded, “Collectively, our findings suggest that TPD technology can target a specific PTM to induce selective degradation of neurodegenerative disease-associated proteins such as p-p38, demonstrating its potential as a therapeutic modality against AD.”

Researchers have been exploring targeted protein degradation as a way to target disease-associated proteins against which inhibitors or other conventional techniques fail. “Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs),” the team said. “Recent progress in the field of targeted protein degradation has proven its immense potential as a novel therapeutic modality in drug discovery.”

However, while such protein degraders have shown some initial promise, things can get complicated if the proteins go through post-processing, or posttranslational modifications, after being formed. But while TPD molecules that recognize and bind to proteins with specific post-translational modifications, such as phosphorylation, may offer a novel strategy to selectively degrade proteins that are pathological because of aberrant PTMs, the team continued, thus far, no TPD technique has been able to target this type of protein. “… a TPD molecule specifically targeting post-translationally modified proteins has not been reported yet.”

One protein that would be particularly advantageous to break down is p38, which is involved in several cellular signaling pathways and is linked to the development of Alzheimer’s disease. Although previous attempts to treat the disease by focusing on p38 have been made—including a drug candidate that went through two phases of clinical trials —they suffered from off-target effects and limited efficacy. “The therapeutic potential of inhibiting p38 in neurodegeneration has been investigated in several clinical trials, but there has been no success yet partly due to off-target effects and insufficient efficacy,” the team noted. Like many proteins, p38 goes through posttranslational modifications, including phosphorylation to form p-p38.

Phosphorylation adds a phosphate group to the protein, activating it and changing its shape. By homing in on this form of p38, it’s possible that treatment could be made more specific. So, the researchers set out to create, for the first time, a protein degrader that could target and break down p-p38, and potentially offer a new avenue for treating Alzheimer’s disease.

The team screened several compounds specific for p-p38, eventually identifying a molecule designated PRZ-18002, which selectively induced degradation of p-p38 over both similar proteins and its inactivated form. In fact, PRZ-18002 maintained its selectivity even when tested against 96 different protein kinases similar to p38. When delivered to the brains of mouse models of Alzheimer’s disease, the compound downregulated the p38 pathway, improving cognitive abilities, including spatial reasoning, and disease-related brain chemistry, such as the accumulation of amyloid-beta plaques. “Importantly, we found that PRZ-18002 induced selective in vivo degradation of p-p38 and ameliorated neurodegenerative symptoms including neuroinflammation, Aβ deposition, and memory loss,” the scientists wrote. “… PRZ-18002 diminished deposition of Aβ, hyper-phosphorylation of tau, reactive gliosis, and production of proinflammatory cytokines, thus resulting in improved spatial memory and learning in the AD mouse model.”

The researchers say that this work could someday provide a novel treatment for Alzheimer’s disease and open up opportunities for future treatments of other diseases that also involve modified proteins. “In this report, we have demonstrated that phosphorylated p38 can be targeted and sequentially eliminated by a TPD approach,” they concluded. “To the best of our knowledge, we have presented, for the first time, a chemical degrader that directly targets a specific PTM of a disease-associated protein for proteasomal degradation, further advancing a TPD approach as a novel therapeutic strategy.”

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