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Alzheimer's Disease: Could Ubiquitin be Part of a Cure?

by: Katelyn Roberts and Dahmane Ouazia 


When combing the volumes for patient stories available online I was taken aback by the profound impact an Alzheimer’s Disease (AD) diagnosis has on an individual and his or her loved ones. Alzheimer’s Disease is much more than just memory loss. Many of the stories included terrible bouts of depression and severe personality changes. The touching story of Roger described a man who lost interest in hobbies, friends, and family soon after retirement. After prescribing antidepressants and seeing no improvement, his doctors diagnosed him with AD. Social isolation and loneliness are associated with a weakened immune system and heart disease. The human toll of Alzheimer’s Disease is widespread and growing. With nearly half a million new cases of AD diagnosed every year, the need for novel therapeutics has never been greater. No cure has been found for AD; the only drugs available are cholinesterase inhibitors and a glutamate modulator, which alleviate symptoms but eventually become ineffective as the disease progresses. In fact, AD has one of the worst drug failure rates; from 2002 to 2012, only one out of 244 Alzheimer's drug candidates was approved by the FDA -- 99.6% failure. Namzaric, the most recently approved AD drug (2004), is merely a combination of two earlier (1990s) drugs, one from each class. Researchers are looking for new ways to treat AD. A breakthrough drug would not only treat the underlying disease, but also stop or delay the cell damage that eventually leads to disease progression. Most new AD drugs in clinical trial are either BACE inhibitors or monoclonal antibodies, both of which address plaque buildup in the brain, but none of these have made it to the market. Roche recently halted their phase III clinical trial, indicating conventional inhibitor or antibody strategies are ineffective therapeutics. The unmet need for neurodegenerative therapeutics remains. A revolutionary approach is needed, one that harnesses the native biology to degrade disease-associated proteins.


                                                                                      

                                                                           https://www.express.co.uk/life-style/health/554224/Loneliness-elderly-threat-public-health-warns-two-charities

 

Engineering a protein degrader

Recently the ubiquitin proteasome system (UPS) has attracted increased attention from the pharmaceutical industry. Initially developed at Yale in 2001, proteolysis targeting chimeras (PROTACs) are engineered molecules designed to hijack the UPS components and degrade specific unwanted proteins. Although the advantages of protein degradation by a PROTAC molecule has been known for years, it is only recently that PROTACs have been widely appreciated as a viable way to modulate protein levels. A PROTAC is a two-headed molecule designed to engage an E3 ligase (the ubiquitin conjugating enzyme of the UPS) on one end and to specifically bind the desired target protein on the other end, resulting in ubiquitination of the target protein and subsequent proteasomal degradation (see the Figure below). This technology has the potential to eliminate previously “undruggable” disease associated proteins, many of which lack enzymatic activity that could be inhibited for therapeutic effect. Researchers hope that the specific binding interactions of PROTAC molecules will result in less toxicity and fewer side effects than are seen with inhibitors currently used on patients. PROTAC technology has clear advantages over traditional inhibitory small molecules; the field is still in its infancy, however, and researchers must overcome many obstacles before PROTAC therapeutics enter the clinic. 



                                                                           


Neurodegenerative disease association

Proteinopathies are diseases characterized by the presence of misfolded proteins. This large group includes many cancers as well as neurodegenerative diseases. Disorders such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease and ALS (Lou Gehrig’s Disease) are characterized by aggregated proteins in increased numbers of neuronal cells in the brainas the disease progresses. The UPS  has long been a prime suspect for early involvement in these neurodegenerative diseases. Preclinical studies on PROTAC degraders show that they can penetrate the blood-brain barrier. While a dysfunctional or overwhelmed UPS may contribute to the accumulation of aggregated proteins, with the aid of PROTAC molecules it could be part of the solution. 

                                                                                       

                                                           Jucker, M. & Walker, L. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51 (2013).


PROTAC research has taken off

Many pharmaceutical companies are investing heavily in PROTAC research and there has been a considerable increase in publications in this field. This research activity has generated excitement over the promise of PROTAC drugs, but it has also uncovered challenges. Until recently, very few molecules that target an E3 ligase had been identified; most were derivatives of Thalidomide. However, recent advancements in UPS research have generated numerous specific, low molecular weight E3 binders that have given the PROTAC field new life. One challenge for PROTAC researchers is the size of the molecule. Because of their bi-functionality, PROTACs are much larger than traditional enzyme inhibitors or receptor agonists/antagonists. Current efforts are being made to streamline the bifunctional PROTAC molecules and thereby increase their ability to enter cells. Another major challenge in PROTAC drug development is monitoring the reaction. It is critical to observe the ubiquitination of the target along with its subsequent degradation to determine the efficacy of the experimental PROTAC drug. Current methods are low-throughput and do not address the ubiquitination question. LifeSensors has developed a high-throughput assay to monitor ubiquitination and degradation of a target protein. This technology will help to propel PROTAC research and bring this innovative approach to drug discovery to the clinic. 


                                                                                                      

                        Zou, Yutian, et al. “The PROTAC Technology in Drug Development.” The Canadian Journal of Chemical Engineering, Wiley-Blackwell, 2 Jan. 2019, onlinelibrary.wiley.com/doi/epdf/10.1002/cbf.3369.


How can LifeSensors assist your research?

Any cure for any disease starts with identifying specific biomarkers and specific therapeutic targets. LifeSensors’ newly developed TUBE-based Mass Spectrometry platform is a powerful tool to identify biomarkers for neurodegenerative diseases. Comparing the ubiquitination profiles of diseased versus healthy tissues will ultimately result in identifying biomarkers that could translate into therapeutic targets, around which PROTAC strategies can be built. These potential protein targets, which are elevated in the disease state and contribute to its pathology, escape recognition by the components of the UPS; finding the right molecule that will bring the UPS components into contact with the target protein may be the answer to curing the disease. As a quantitative strategy, TUBE-based Mass Spectrometry technology makes it possible to assess the effect of a given PROTAC drug on the amount and extent of ubiquitination of the target protein as well as other proteins in the tissue sample. Moreover, Lifesensors has developed high throughput PROTAC screens (UbiQuant Technology) through which multiple PROTAC drugs can be tested on a protein of interest (therapeutic target). The Ubiquant technology is based on the use of multi-well plates with TUBEs anchored to the bottom of the wells. TUBEs bind specifically to ubiquitinated proteins, whereas non-ubiquitinated proteins are discarded. The ubiquitination levels of the protein of interest is subsequently quantified by an antibody that binds specifically to the target protein and emits a signal proportional to the amount of that specific protein in the well. The Ubiquant technology represents a very rapid and robust tool that will accelerate the development of a PROTAC-based drug as a cure for neurodegenerative diseases. LifeSensors continues to develop revolutionary approaches to PROTAC-based drugs targeting the UPS. Please contact LifeSensors to see how it can help you bring your ubiquitin research to the next level.

 

References

-Cacioppo JT, Hawkley LC. Perceived social isolation and cognition. Trends Cogn Sci. 2009;13(10):447-54.

-Dantuma, Nico, and Bott, Laura. “The Ubiquitin-Proteasome System in Neurodegenerative Diseases: Precipitating Factor, Yet Part of the Solution.” Frontiers, Frontiers, 9 July 2014, www.frontiersin.org/articles/10.3389/fnmol.2014.00070/full.

-Jucker, M. & Walker, L. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51 (2013).

-Kleiger, Gary et al. “Perilous Journey: a tour of the ubiquitin-proteasome”. Trends in Cell Biology , Volume 24 , Issue 6 , 352 – 359 (2014).

 

-Shurkin, Joel. “Alzheimer's Drug Trials Keep Failing -- It May Be Because We Don't Understand the Disease.” Inside Science, 13 Mar. 2018, www.insidescience.org/news/Alzheimer%27s-Drug-Trials-Keep-Failing.

 

-Taylor, Nick. “Roche Halts Phase 3 Anti-Abeta Alzheimer's Test as AD Flops Rack Up.” FierceBiotech, 30 Jan. 2019, www.fiercebiotech.com/biotech/roche-halts-phase-3-anti-abeta-alzheimer-s-trials-for-futility.

-Zou, Yutian, et al. “The PROTAC Technology in Drug Development.” The Canadian Journal of Chemical Engineering, Wiley-Blackwell, 2 Jan. 2019, onlinelibrary.wiley.com/doi/epdf/10.1002/cbf.3369.

 

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