New technique shows in detail where drug molecules hit their targets in
the body

Date:
April 29, 2022
Source:
Scripps Research Institute
Summary:
Scientists 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.



FULL STORY ========================================================================== 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.


========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zhengyuan Pang, Michael A. Schafroth, Daisuke Ogasawara, Yu Wang,
Victoria Nudell, Neeraj K. Lal, Dong Yang, Kristina Wang, Dylan M.

Herbst, Jacquelyn Ha, Carlos Guijas, Jacqueline L. Blankman,
Benjamin F.

Cravatt, Li Ye. In situ identification of cellular drug targets
in mammalian tissue. Cell, 2022; DOI: 10.1016/j.cell.2022.03.040 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220429163640.htm

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