Degrading modified proteins could treat Alzheimer’s disease and other ‘unmedicated’ diseases

Summary: Researchers have developed a compound capable of targeting and breaking down a post-transitionally modified protein associated with Alzheimer’s disease.

Source: American chemical society

Some diseases, including Alzheimer’s disease, are currently considered “incurable” because traditional small molecule drugs cannot interfere with disease-causing proteins. But a new technique that specifically targets and breaks down certain proteins — rather than just interfering with them — may offer a route to treatment.

Researchers reporting in AEC Core Sciences have, for the first time, designed a compound that targets and breaks down a post-translationally modified protein closely associated with Alzheimer’s disease.

Researchers have explored targeted protein degradation (TPD) as a means of reaching hard-to-treat proteins, namely those for which inhibitors or other conventional techniques fail.

Although these degraders showed initial promise, things can get complicated if the proteins undergo “post-processing” or post-translational modifications after they are formed. So far, no PDT technique has been able to target this type of protein.

A protein that it would be particularly advantageous to degrade is p38, involved in several cell signaling pathways and linked to the development of Alzheimer’s disease.

Although previous attempts to treat the disease focusing on p38 have been made – including a drug candidate that has gone through two phases of clinical trials – they have suffered from off-target effects and limited efficacy.

But like many proteins, p38 undergoes post-translational modifications, including phosphorylation, to form p-p38. This adds a phosphate group to the protein, activating it and changing its shape.

By focusing on this form instead, the treatment could be made more specific. Thus, Nam-Jung Kim, Kyung-Soo Inn, Jong Kil Lee and their colleagues wanted, for the first time, to create a protein degrader that could target and break down p-p38, and potentially offer a new route for the treatment of Alzheimer’s disease.

It shows a brain
A protein that it would be particularly advantageous to degrade is p38, involved in several cell signaling pathways and linked to the development of Alzheimer’s disease. Image is in public domain

The team screened several p-p38-specific compounds, ultimately finding PRZ-18002, which selectively induces the degradation of p-p38 on similar proteins and its inactivated form. In fact, PRZ-18002 maintained its selectivity even when tested against 96 different p38-like protein kinases.

When administered 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 accumulation of beta-amyloid plaques.

The researchers say this work could one day provide a new treatment for Alzheimer’s disease and open up opportunities for future treatments of other diseases that also involve modified proteins.

Funding: The authors acknowledge funding from the Korean Government National Research Foundation (MSIT) and the Basic Research Laboratory Program and Medical Research Center Program of the National Research Foundation funded by the Korean Ministry of Science, ICT and of the future.

About this Alzheimer’s disease research news

Author: Kate Cottingham
Source: American chemical society
Contact: Katie Cottingham – American Chemical Society
Picture: Image is in public domain

Original research: Free access.
“Chemical Reduction of Mitogen-Activated Phosphorylated Protein Kinase p38 (MAPK) as a Novel Approach for the Treatment of Alzheimer’s Disease” by Nam-Jung Kim et al. AEC Core Sciences

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Chemical knockdown of mitogen-activated p38 phosphorylated protein kinase (MAPK) as a new approach for the treatment of Alzheimer’s disease

Targeted protein degradation (TPD) offers unique advantages over gene silencing in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or post-translational modifications (PTMs). ) outliers.

Here we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces the degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner.

Since p38 MAPK activation plays a central role in the pathophysiology of Alzheimer’s disease (AD), selective degradation of p-p38 may be an attractive therapeutic option for the treatment of AD.

In the 5xFAD transgenic mouse model of AD, intranasal treatment with PRZ-18002 reduces p-p38 levels and attenuates microglia activation and beta-amyloid (Aβ) deposition, leading to subsequent improvement in l spatial learning and memory.

\ Collectively, our results suggest that PRZ-18002 ameliorates AD pathophysiology via the selective degradation of p-p38, highlighting a novel therapeutic modality of PDT that targets a specific PTM to induce selective degradation of the AD-associated protein. neurodegenerative disease.

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