Home Medizin Forscher stellen einen bahnbrechenden Ansatz zur Bekämpfung neurodegenerativer Erkrankungen vor

Forscher stellen einen bahnbrechenden Ansatz zur Bekämpfung neurodegenerativer Erkrankungen vor

von NFI Redaktion

A team of researchers from Northwestern University and the University of Wisconsin-Madison has introduced a groundbreaking approach to combat neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis (ALS).

In a new study, researchers discovered a novel way to enhance the body’s antioxidant response, which is crucial for cellular protection against oxidative stress associated with many neurodegenerative diseases.

The study was published today (February 16) in the journal Advanced Materials.

Leading the work were Nathan Gianneschi, Jacob & Rosaline Cohn Professor of Chemistry at the Weinberg College of Arts and Sciences at Northwestern University, and Jeffrey A. Johnson and Delinda A. Johnson of the University of Wisconsin-Madison School of Pharmacy.

Combating Neurodegenerative Diseases

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

The study focuses on disrupting the Keap1/Nrf2 protein-protein interaction (PPI), which plays a role in the body’s antioxidant response. By preventing the degradation of Nrf2 through selective inhibition of its interaction with Keap1, the research promises to alleviate the cell damage underlying these debilitating conditions.

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

Limitations of Current Therapeutics

The research team tackled one of the most challenging aspects of treating neurodegenerative diseases: precisely targeting PPIs within the cell. Conventional methods, including low molecule inhibitors and peptide-based therapies, have failed due to lack of specificity, stability, and cellular uptake.

The study presents an innovative solution: Protein-like polymers, or PLPs, are high-density, brush-like macromolecular architectures synthesized through ring-opening metathesis polymerization (ROMP) of monomers based on norbornenyl peptides. These spherical, proteomimetic structures have 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 advancement. By preventing Keap1 from marking Nrf2 for degradation, Nrf2 accumulates in the cell nucleus, activates the Antioxidant Response Element (ARE), and drives the expression of detoxifying and antioxidant genes. This mechanism effectively enhances the cellular antioxidant response and provides an effective therapeutic strategy against the oxidative stress involved in many neurodegenerative diseases.

The Innovation Behind Protein-like Polymers

PLPs developed by Gianneschi’s team could represent a major breakthrough in containing or reversing damage and offering hope for improved treatments and outcomes.

The team’s research focuses on activating processes crucial to the body’s antioxidant response and provides a novel solution. The team provides a robust, selective method that enables improved cellular protection and offers a promising therapeutic strategy for a range of diseases, including neurodegenerative diseases.

„With modern polymer chemistry, we can begin to think about mimicking complex proteins. The promise lies in developing a new modality for designing therapeutics. This could be a way to combat diseases such as Alzheimer’s and Parkinson’s, among others, where conventional approaches have faced challenges.“


Nathan Gianneschi, Jacob & Rosaline Cohn Professor of Chemistry at Northwestern University’s Weinberg College of Arts and Sciences

This approach not only represents a significant advancement in the targeted combat of transcription factors and disrupted proteins but also demonstrates the versatility and potential of PLP technology to revolutionize the development of therapeutics. The modularity and effectiveness of the technology in inhibiting the Keap1/Nrf2 interaction underscore its therapeutic potential and its use as a tool to study the biochemistry of these processes.

A Collaborative Effort

Gianneschi’s team highlighted the collaborative nature of the study, working closely with experts from various disciplines to demonstrate the enormous potential of combining materials science and cell biology to address complex medical challenges.

„Professor Gianneschi and colleagues contacted us regarding the use of this novel PLP technology in neurodegenerative diseases based on 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 to Nrf2 activation and immediately agreed to initiate this joint effort, which led to the generation of great data and this publication.“

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

Impact

With the development of this innovative technology, Gianneschi 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, but also opening new avenues to combat some of the most challenging and devastating neurodegenerative diseases faced by society today. As this research progresses towards clinical application, it could soon offer new hope for those suffering from diseases with oxidative stress such as Alzheimer’s and Parkinson’s.

„By controlling materials at the single nanometer scale, we are opening new avenues in the fight against diseases that are becoming more prevalent than ever but remain untreated,“ said Gianneschi. „This study is just the beginning. We look forward to the possibilities as we continue to explore and expand the development of macromolecular drugs using our PLP platform, which are capable of mimicking some aspects of proteins.“

Quelle:

Zeitschriftenreferenz:

Carrow, KP, et al. (2024). Inhibition of the Keap1/Nrf2 Protein-Protein Interaction with Protein-like Polymers. Advanced Materials. doi.org/10.1002/adma.202311467.

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