Sony Pixel Power calrec Sony

April 27, 2022

28/04/2022

New technique shows in detail where drug molecules hit their targets in the body Devised by Scripps Research scientists, the new method could speed the development of many new drugs.

April 27, 2022

LA JOLLA, CA Scientists at Scripps Research have invented a way to image, across different tissues and with higher precision than ever before, where drugs bind to their targets in the body. The new method could become a routine tool in drug development.

Described in a paper in Cell on April 27, 2022, the new method, called CATCH, attaches fluorescent tags to drug molecules and uses chemical techniques to improve the fluorescent signal. The researchers demonstrated the method with several different experimental drugs, revealing where even within individual cells the drug molecules hit their targets.

This method ultimately should allow us, for the first time, to see relatively easily why one drug is more potent than another, or why one has a particular side effect while another one doesn't, says study senior author Li Ye, PhD, assistant professor of neuroscience at Scripps Research and The Abide-Vividion Chair in Chemistry and Chemical Biology.

The study's first author, Zhengyuan Pang, is a graduate student in the Ye lab. The study also was a close collaboration with the laboratory of Ben Cravatt, PhD, Gilula Chair of Chemical Biology at Scripps Research.

The unique environment at Scripps Research, where biologists routinely work together with chemists, is what made the development of this technique possible, Ye says.

Understanding where drug molecules bind their targets to exert their therapeutic effects and side effects is a basic part of drug development. However, drug-target interaction studies traditionally have involved relatively imprecise methods, such as bulk analyses of drug-molecule concentration in entire organs.

The CATCH method involves the insertion of tiny chemical handles into drug molecules. These distinct chemical handles don't react with anything else in the body, but do allow the addition of fluorescent tags after the drug molecules have bound to their targets. In part because human or animal tissue tends to diffuse and block the light from these fluorescent tags, Ye and his team combined the tagging process with a technique that makes tissue relatively transparent.

In this initial study, the researchers optimized and evaluated their method for covalent drugs, which bind irreversibly to their targets with stable chemical bonds known as covalent bonds. This irreversibility of binding makes it particularly important to verify that such drugs are hitting their intended targets.

The scientists first evaluated several covalent inhibitors of an enzyme in the brain called fatty acid amide hydrolase (FAAH). FAAH inhibitors have the effect of boosting levels of cannabinoid molecules, including the bliss molecule anandamide, and are being investigated as treatments for pain and mood disorders. The scientists were able to image, at the single-cell level, where these inhibitors hit their targets within large volumes of mouse brain tissue, and could easily distinguish their different patterns of target engagement.

In one experiment, they showed that an experimental FAAH inhibitor called BIA-10-2474, which caused one death and several injuries in a clinical trial in France in 2016, engages unknown targets in the midbrain of mice even when the mice lack the FAAH enzyme offering a clue to the source of the inhibitor's toxicity.

In other tests demonstrating the unprecedented precision and versatility of the new method, the scientists showed that they could combine drug-target imaging with separate fluorescent-tagging methods to reveal the cell types to which a drug binds. They also could distinguish drug-target engagement sites in different parts of neurons. Finally, they could see how modestly different doses of a drug often strikingly affect the degree of target engagement in different brain areas.

The proof-of-principle study is just the beginning, Ye emphasizes. He and his team plan to develop CATCH further for use on thicker tissue samples, ultimately perhaps whole mice. Additionally, they plan to extend the basic approach to more common, non-covalently-binding drugs and chemical probes. On the whole, Ye says, he envisions the new method as a basic tool not only for drug discovery but even for basic biology.

In situ Identification of Cellular Drug Targets in Mammalian Tissue was co-authored by Zhengyuan Pang, Michael Schafroth, Daisuke Ogasawara, Yu Wang, Victoria Nudell, Neeraj Lal, Dong Yang, Kristina Wang, Dylan Herbst, Jacquelyn Ha, Carlos Guijas, Jacqueline Blankman, Benjamin Cravatt and Li Ye all of Scripps Research during the study.

The study was funded in part by the National Institutes of Health (DP2DK128800, DK114165, DK124731, DA033760), the Whitehall Foundation, the Baxter Foundation, and the Dana Foundation.

Chemistry Ye, Li
LINK: https://www.scripps.edu/news-and-events/press-room/2022/20220427-ye-ca...
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...