Sony Pixel Power calrec Sony

December 30, 2019

31/12/2019

RNA-targeting strategy successfully blocks a vexing driver of Parkinson's disease A new drug-like compound prevents the body from producing a protein thats often at the root of Parkinsons.

December 30, 2020

JUPITER, FLA Scientists at Scripps Research have developed a drug-like compound that selectively prevents production of the protein underlying most causes of Parkinson's disease, alpha-synuclein.

The study underscores the untapped potential of addressing diseases mediated by undruggable proteins via the messenger RNAs that encode them.

To be published the week of Dec. 30 in the Proceedings of the National Academies of Sciences, the study is authored by Scripps Research chemistry professor Matthew D. Disney, PhD, and graduate student Peiyuan Zhang, and their colleagues.

If DNA serves as the code of life, genes within DNA provide the code for specific proteins. For a gene to actually encode a protein, however, it must first be transcribed with the help of messenger RNA. The messenger RNA serves as a template for protein production, a process called translation, which is orchestrated by molecular machines called ribosomes.

Disney's alpha-synuclein compound, which he named synucleozid, stops the ribosome from detecting the messenger RNA template, thus preventing the translation or printing of the alpha-synuclein protein. The Scripps Research team collaborated on the study with a team from Rutgers University led by M. Maral Mouradian, MD, director of the Institute for Neurological Therapeutics.

We showed not only that we can inhibit the translation of alpha-synuclein, which is an important protein in Parkinson's disease and dementia, but also that this compound can stop its messenger RNA from being recognized by a ribosome, Disney says. In other words, the compound doesn't allow the messenger RNA to be made into the alpha-synuclein protein. We believe this unique mechanism is broadly applicable.

Disney has spent more than a decade building technologies capable of identifying drug-like compounds to do this. A system he invented called Inforna computationally uses genetic sequence to predict complementary small molecule-RNA interactions.

Most drugs on the market work by binding to problematic proteins to limit their ability to cause harm. However, for a drug to bind, those proteins must have stable structures with favorable binding pockets.

The alpha-synuclein protein is one example of many in the genome that have confounded scientists' efforts to bind with medications, due to their undefined structure.

In fact, the so-called druggable genome is currently comprised of only about 3,000 genes out of an estimated 20,000 protein-coding genes. Disney says his research suggests that many undruggable proteins are transcribed by RNA that do have stable structures, meaning the RNA should be druggable, offering an effective workaround.

We are applying this across a number of disease indications, with our priority being applying these approaches to the diseases that have the most urgent medical need, Disney says.

Parkinson's disease is clearly among them. With an estimated 1 million people in the United States alone living with the condition, at an estimated cost of over $50 billion annually, Parkinson's causes chronic, progressive disability due to the death of dopamine-producing cells in the brain. The symptoms may include slowness of movements, impaired coordination, limb and trunk stiffness, tremor, and eventually dementia and psychiatric manifestations.

Symptoms emerge as the alpha-synuclein protein accumulates in brain cells, misfolding and aggregating to form clumps called Lewy bodies and Lewy neurites. Certain forms of these aggregates are toxic and eventually lead to the cell's death.

Mouradian says down-regulating production of alpha-synuclein may have therapeutic promise.

The precise molecular mechanisms driving Parkinson's disease remain to be fully elucidated. However, the amount of alpha-synuclein protein levels is an important factor in its pathologic misfolding and aggregation, initiating a cascade of events that lead to neuronal damage and Parkinson's symptoms, Mouradian says. Therefore, it stands to reason that reducing the amount of alpha-synuclein protein can mitigate this disease-causing cascade, and slow down or stop disease progression. Identification of this alpha-synuclein messenger RNA-targeting probe will enable us to evaluate the therapeutic value of reducing alpha-synuclein production in patients.

Many people with Parkinson's respond for a time to therapeutics that include dopamine replacement. But adding back dopamine doesn't protect the nervous system from the progressively worsening disease process, and introduces its own set of sometimes serious side-effects.

We wanted to see if we could inhibit this protein from even being made by targeting the messenger RNA that encodes it, Disney says.

The benefit of choosing a small molecule to do this rather than an RNA-binding oligonucleotide is that a therapeutic agent must be very, very small to cross the blood-brain barrier. It must also be selective, and apparently these starting compounds are selective.

We found the molecule was very selective at the RNA level. We also studied the effects at the protein level, and the molecule was also selective on that level, Disney says.

But Disney notes that this is a proof-of-concept study, and that a long road lies ahead before Synucleozid might become a Parkinson's drug candidate that can move into clinical trials in humans.

We are just at the beginning here, and there is much work to do Disney says. We are showing that if you can inhibit a protein from being made, that may be advantageous over waiting to address its role in disease until after it is already made.

The study, Trans
LINK: https://www.scripps.edu/news-and-events/press-room/2019/20191230-disne...
See more stories from scripps

More from Scripps

13/03/2024

March 13, 2024

New computational strategy boosts the ability of drug designers to target proteins inside the membrane Customized-design approach could streamline the design of...

29/02/2024

February 29, 2024

Scripps Research scientists reveal how first cells could have formed on Earth New phospholipid discovery brings researchers closer to understanding how primordi...

29/02/2024

February 28, 2024

How molecular handedness emerged in early biology Scripps Research chemists fill a major gap in origin-of-life theories. February 28, 2024 LA JOLLA, CA Mole...

22/02/2024

February 21, 2024

Snaking toward a universal antivenom Scripps Research scientists discovered antibodies that protect against a host of lethal snake venoms. February 21, 2024 ...

06/02/2024

February 06, 2024

Calibr-Skaggs announces expansion of option and license agreement with AbbVie to develop novel cell therapies for solid tumors and autoimmune diseases AbbVie...

26/01/2024

January 25, 2024

Re-energizing mitochondria to treat Alzheimer's disease Scripps Research team restored neuron-to-neuron connections in human cells. January 25, 2024 LA JO...

24/01/2024

January 04, 2024

100 years of Science Changing Life: Scripps Research celebrates a century of transforming human health For the last century, institute leaders and renowned scie...

23/01/2024

January 23, 2024

New technology lets researchers track brain cells' off switches The method could shed light on what goes awry in numerous brain conditions when neurons ar...

09/01/2024

January 08, 2024

Three decades of giving: Announcing the Calibr-Skaggs Institute for Innovative Medicines The ALSAM Foundation, founded by the Skaggs family, provides lasting g...

04/01/2024

January 03, 2024

Life science entrepreneur Gene Lay joins Scripps Research Board of Directors Lay, founder of the global biotech company BioLegend, brings invaluable experience ...

21/12/2023

December 20, 2023

Taming a plant-derived toxin Scripps Research team modifies the traditional poison picrotoxinin for potential neurological drugs and anti-parasite treatments. ...

19/12/2023

December 18, 2023

Scripps Research Executive Vice President Eric Topol gives TED talk on transformative power of AI in medicine Topol provides an overview of how AI models can i...

13/12/2023

December 12, 2023

New AI-powered algorithm could better assess people's risk of common heart condition Early detection of atrial fibrillation can reduce the risk of stroke an...

07/12/2023

December 06, 2023

Nanoparticle flu vaccine design shows promise in early tests Scripps Research-designed vaccine could provide broad, enduring protection against influenza A str...

16/11/2023

November 15, 2023

Numerous Scripps Research scientists named Highly Cited Researchers Clarivate's annual, global list represents researchers who have demonstrated significant...

07/11/2023

November 06, 2023

Multiple sclerosis drug invented at Scripps Research slows long-term devastating disease progression Late-breaking data reinforces the effectiveness and safety ...

05/10/2023

October 04, 2023

Keren Lasker named a 2023 Moore Inventor Fellow The prestigious award will support Lasker's inventive research in membraneless organelles and their applica...

22/09/2023

September 21, 2023

Michael Bollong named a 2023 Amgen Young Investigator The prestigious award will support Bollong's research identifying new molecular targets and therapeuti...

09/09/2023

September 08, 2023

Philip Dawson receives 2024 American Chemical Society National Award Dawson is honored with the Arthur C. Cope Late Careers Scholar Award for his foundational c...

07/09/2023

September 06, 2023

Scripps Research chemists devise a method for C-H activation of alcohols The method represents a new toolkit for making drugs and other compounds. September 06...

31/08/2023

August 30, 2023

Scripps Research receives $1.5M to surveil infectious disease threats in wastewater Bill & Melinda Gates Foundation award to support the development of multi-pa...

16/08/2023

August 16, 2023

How cold temperatures trigger the brain to boost appetite Scripps Research scientists' discovery could lead to new weight loss and metabolic health treatmen...

08/08/2023

August 07, 2023

Human antibody that targets carfentanil, fentanyl and related opioids reverses overdose effects in preclinical study Scripps Research-developed antibody therapy...

04/08/2023

August 03, 2023

How sensory neurons impact the gut Scripps Research scientists show that the receptor PIEZO2 in sensory neurons controls gut motility and transit time, which a...

26/07/2023

July 26, 2023

AbbVie and Calibr Expand Strategic Collaboration to Advance Several Preclinical and Early-stage Clinical Assets The expanded strategic collaboration will advan...

23/07/2023

July 21, 2023

Scripps Research scientists develop AI-based tracking and early-warning system for viral pandemics Machine-learning system effectively predicts emergence of pro...

19/07/2023

July 19, 2023

Monitoring T cells may allow prevention of type 1 diabetes Scripps Research study shows that analyzing T cells in blood samples could be used to select at-risk ...

19/07/2023

July 18, 2023

Scripps Research mourns passing of leading organic chemist Albert Eschenmoser Eschenmoser pioneered key reactions in synthetic chemistry and shaped the understa...

15/06/2023

June 14, 2023

Scripps Research awarded $46.8 million by NIH to promote human health through innovative translational science and training The Translational Institute is harne...

13/06/2023

June 13, 2023

Scripps Research's Danielle Grotjahn named 2023 Pew Scholar in the Biomedical Sciences The award will support Grotjahn's study of how cells assemble the...

31/05/2023

May 31, 2023

Crossing the ring: new method enables C-H activation across saturated carbocycles Scripps Research chemists add another powerful tool to their molecular editin...

24/05/2023

May 23, 2023

Scripps Research develops behind-the-scenes tool for better biomedical data discovery The new resource makes datasets more discoverable for life science communi...

19/05/2023

May 15, 2023

Scripps Research neuroscientist Hollis Cline elected to American Academy of Arts and Sciences Cline is recognized for her discoveries about the role of sensory ...

19/05/2023

May 18, 2023

Scripps Research's Skaggs Graduate School awards doctoral degrees to 31st graduating class Commencement ceremony will be livestreamed via Zoom and on instit...

13/05/2023

May 12, 2023

A better route to benzocyclobutenes, sought-after building blocks for drugs Scripps Research chemists devise a new, C-H activation-based method for the synthesi...

09/05/2023

May 08, 2023

Renowned Scripps Research professor Jeffery Kelly elected to National Academy of Sciences Kelly's groundbreaking work on protein misfolding has led to thera...

28/04/2023

April 27, 2023

Mirror-image molecules pave new path for cancer drug discovery By comparing how mirror image versions of small molecules impact clusters of proteins, Scripps R...

22/04/2023

April 21, 2023

How alcohol consumption contributes to chronic pain A Scripps Research team showed how both alcohol intake and alcohol withdrawal can lead to increased pain and...

21/04/2023

April 20, 2023

Xin Jin receives dual awards to study autism risk genes in neurodevelopment Major grants from the National Institutes of Health and California Institute for Reg...

20/04/2023

April 19, 2023

Trim the sugar: New HIV vaccine design improves immune response Scripps Research vaccine candidate headed for clinical trials. April 19, 2023 LA JOLLA, CA A...

18/04/2023

April 17, 2023

Therapeutic can seek and destroy potent opioid to treat overdoses Scripps Research chemists developed a new biologic to work against the synthetic opioid carfen...

07/03/2023

March 06, 2023

How heavy alcohol consumption increases brain inflammation The findings by a Scripps Research team point toward a potential new drug target for treating alcohol...

02/03/2023

March 01, 2023

Scientists find human antibodies that can block multiple coronaviruses including SARS-CoV-2 Results from a Scripps Research and UNC team pave the way for a vacc...

28/02/2023

February 28, 2023

$10 million grant funds Scripps Research Alcohol Research Center through its 50th year The five-year grant supports research into the neurobiology of alcohol us...

28/02/2023

February 27, 2023

Immune system drug shows promise in treating alcohol use disorder, a Scripps Research clinical trial reports Scientists at Scripps Research found that apremilas...

23/02/2023

February 16, 2023

Chemically poisoned protein acts as a molecular switch to spur cancer formation The discovery triggered development of a new potential drug to eliminate tumor...

23/02/2023

February 23, 2023

Two new papers demonstrate use of Outbreak.info as one-stop online source for COVID data Scripps Research scientists highlight the need for continued monitorin...

15/02/2023

February 15, 2023

Calibr and Bill & Melinda Gates Medical Research Institute announce licensing agreement for novel candidate tuberculosis treatment compound Calibr transitions i...

08/02/2023

February 07, 2023

Scripps Research Professor Jeffery Kelly awarded 2023 Wolf Prize in Chemistry Kelly receives the prestigious award for his seminal discoveries in protein-foldin...

31/01/2023

January 30, 2023

Experimental anti-depression drug may also be useful in treating alcohol use disorder Investigational, clinical-stage antidepressant MAP4343 shown to reduce alc...