Targeting “undruggable” proteins promises a new approach to treating neurodegenerative diseases

Researchers led by Northwestern University and the University of Wisconsin-Madison have introduced a pioneering approach to combat neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

In a new study, researchers have discovered a new way to improve the body’s antioxidant response, essential for cellular protection against oxidative stress involved in many neurodegenerative diseases.

The study published today in the journal Advanced materials.

Nathan Gianneschi, the Jacob & Rosaline Cohn Professor of Chemistry in Northwestern’s Weinberg College of Arts and Sciences and a member of the International Nanotechnology Institute, led the work with Jeffrey A. Johnson and Delinda A. Johnson of the University of Wisconsin- Madison School of Pharmacy.

Targeting neurodegenerative diseases

Alzheimer’s disease, characterized by the accumulation of beta-amyloid plaques and tau protein tangles; Parkinson’s disease, known for its loss of dopamine neurons and the presence of Lewy bodies; and ALS, involving motor neuron degeneration, all share a common thread of oxidative stress contributing to disease pathology.

The study focuses on the disruption of the Keap1/Nrf2 protein-protein interaction (PPI), which plays a role in the body’s antioxidant response. By preventing Nrf2 degradation through selective inhibition of its interaction with Keap1, the research shows promise in mitigating the cellular damage that causes these debilitating conditions.

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

Limitations of current therapies

The research team addressed one of the most challenging aspects of treating neurodegenerative diseases: precisely targeting PPIs within the cell. Traditional methods, including small molecule inhibitors and peptide-based therapies, have failed due to 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 via ring-opening metathesis polymerization (ROMP) of norbornenyl-peptide-based monomers. These proteomimetic globular structures feature bioactive peptide side chains that can penetrate cell membranes, exhibit remarkable stability, and resist proteolysis.

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

The Innovation Behind Protein-Like Polymers

PLPs, developed by Gianneschi’s team, could represent a significant advance in stopping or reversing damage, offering hope for improved treatments and outcomes.

By focusing on the challenge of activating processes crucial to the body’s antioxidant response, the team’s research offers a new solution. The team proposes a robust and selective method enabling enhanced cellular protection and offering a promising therapeutic strategy for a range of diseases, including neurodegenerative diseases.

“Thanks to modern polymer chemistry, we can start to think about mimicking complex proteins,” Gianneschi said. “The promise lies in the development of a new modality for designing therapeutic products. This could be a way to combat diseases like Alzheimer’s and Parkinson’s, among others, for which traditional approaches have failed difficulties.”

This approach not only represents a significant advance in targeting transcription factors and disordered proteins, but also highlights the versatility and potential of PLP technology to revolutionize therapeutic product development. The modularity and effectiveness of the technology in inhibiting the Keap1/Nrf2 interaction highlight its potential for impact as a therapeutic tool, but also as a tool for studying the biochemistry of these processes.

A collaboration of minds

Highlighting the collaborative nature of the study, Gianneschi’s team worked closely with experts from across disciplines, illustrating the rich potential of combining materials science with cell biology to address complex medical challenges.

“We were contacted by Professor Gianneschi and colleagues proposing to use this new PLP technology in neurodegenerative diseases due to our previous work on Nrf2 in models of Alzheimer’s disease, Parkinson’s disease, ALS and Huntington’s disease,” said Jeffrey Johnson. “We had never heard of this approach for Nrf2 activation and immediately agreed to launch this collaborative effort which led to the generation of excellent data and this publication.”

This partnership highlights the importance of interdisciplinary research in the development of new therapeutic modalities.

Impact

With the development of this innovative technology, Gianneschi and his colleagues at the International Institute of Nanotechnology and the Johnson Lab at the University of Wisconsin-Madison are not only advancing the field of medicinal chemistry, they are opening new avenues to combat against some of the most challenging and devastating neurodegenerative diseases facing society today. As this research progresses toward clinical applications, it may soon offer new hope to people suffering from oxidative stress-related diseases such as Alzheimer’s and Parkinson’s.

“By controlling materials at the nanometer scale, we open up new possibilities in the fight against diseases that are more widespread than ever, but which remain incurable,” Gianneschi said. “This study is just the beginning. We are excited about the possibilities as we continue to explore and expand the development of macromolecular drugs, capable of mimicking aspects of proteins using our PLP platform.”