Targeting ‘undruggable’ proteins promises new approach for treating neurodegenerative diseases

Researchers led by Northwestern University and University of Wisconsin Medicine have introduced a breakthrough approach aimed at combating neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

In a new study, researchers discovered a new way to boost the body’s antioxidant response, which is important for cellular protection against oxidative stress found in many people. Neurodegenerative diseases.

The study was published today in the journal Advanced content.

Nathan Gianshi, the Jacob and Rosalyn Cohen Professor of Chemistry at Northwestern’s Weinberg College of Arts and Sciences and a member of the International Institute for Nanotechnology, led the work with Jeffrey A. Johnson and Delinda A. Johnson of the University of Wisconsin School of Medicine. Pharmacy.

Targeting neurodegenerative diseases

Alzheimer’s disease, characterized by the accumulation of beta-amyloid plaques and tau protein tangles. Parkinson’s disease is known for the loss of dopaminergic neurons and the presence of Lewy bodies. and ALS, which involves the degeneration of motor neurons, all share a common thread of oxidative stress that contributes to the pathology of the disease.

The study focused on disrupting Keap1/Nrf2. Protein-protein interactions (PPI), which plays a role in the body’s antioxidant response. By inhibiting the degradation of Nrf2 through selective inhibition of its interaction with Keap1, the research holds promise for reducing the cellular damage that underlies these debilitating conditions.

“We’ve established Nrf2 as a primary target for the treatment of neurodegenerative diseases over the past two decades, but this new approach to activating the pathway is critical to developing disease-modifying therapies,” said Jeffrey Johnson. Holds great promise,” said Jeffrey Johnson.

Limitations of current treatments

The research team set out to solve one of the most challenging aspects of treating neurodegenerative disease: the precise targeting of PPIs within the cell. Traditional approaches, including small-molecule inhibitors and peptide-based therapies, have been limited by lack of specificity, stability, and cellular uptake.

The study introduces an innovative solution: protein-like polymers, or PLPs, are high-density brush macromolecular architectures synthesized by ring-opening metathesis polymerization (ROMP) of norbornyl peptide-based monomers. These globular, proteomimetic structures display bioactive peptide side chains that can penetrate cell membranes, exhibit remarkable stability, and resist proteolysis.

This targeted approach to inhibit Keap1/Nrf2 PPI represents a significant leap forward. By preventing Keap1 from marking Nrf2 for degradation, Nrf2 accumulates in the nucleus, activates the antioxidant response element (ARE) and drives the expression of detoxifying and antioxidant genes. This mechanism effectively enhances the cellular antioxidant response, providing a powerful therapeutic strategy against oxidative stress involved in many neurodegenerative diseases.

The innovation behind protein-like polymers

PLPs, developed by Giannishi’s team, may represent a major breakthrough in preventing or reversing damage, offering the promise of improved treatments and outcomes.

Focusing on the challenge of activating a process critical to the body’s antioxidant response, the team’s research offers a novel solution. The team provides a robust, selective method that improves cellular protection and offers a promising therapeutic strategy for a number of diseases, including neurodegenerative conditions.

“With advanced polymer chemistry, we can start to think about mimicking complex proteins,” Gianshi said. “The promise lies in the development of a new approach to treatment design. This could be a way to tackle diseases like Alzheimer’s and Parkinson’s where traditional methods are struggling.”

This approach not only represents a significant advance in targeting. Transcription factors and disordered proteins, but also demonstrates the versatility of PLP technology and its potential to revolutionize therapeutic development. The modularity and utility of the technology in blocking the Keap1/Nrf2 interaction underscores the potential for its impact as a therapeutic, but also as a tool to study the biochemistry of these processes.

A collaboration of minds

Highlighting the collaborative nature of the study, Giannishi’s team worked with experts from all disciplines, illustrating the powerful potential of combining materials science with cellular biology to address complex clinical challenges.

“We were approached by Professor Gianshi and colleagues to apply this novel PLP technology to neurodegenerative diseases because of our previous work on Nrf2 in models of Alzheimer’s disease, Parkinson’s disease, ALS and Huntington’s disease,” said Jeffrey Johnson. suggested to do.” “We had never heard of this approach to Nrf2 activation and immediately agreed to start this collaborative effort that led to the great data and the creation of this publication.”

This partnership underscores the importance of interdisciplinary research in developing new therapeutic approaches.

Effects of

With the development of this cutting-edge technology, Gianshi and his colleagues at the International Institute for Nanotechnology and the Johnson Lab at the University of Wisconsin-Madison are not only advancing the field of medicinal chemistry, they are opening some new avenues. . The most challenging and devastating neurodegenerative diseases facing society today. As this research moves toward clinical application, it may soon offer new hope for those suffering from the disease. Oxidative stress such as Alzheimer’s and Parkinson’s diseases.

“By controlling materials at the scale of a single nanometer, we are opening up new possibilities in the fight against diseases that are more prevalent than ever, yet incurable,” Gianshi said. “This study is just the beginning. We are excited about the possibilities as we continue to develop and expand macromolecular drugs, which are able to mimic certain aspects of proteins using our PLP platform.”