The New Method Represents Drugs' Targets in a New Low

The New Method Represents Drugs' Targets in a New Low ...

Scripps Research has developed a way to image, across different tissues, and with higher precision than ever before, where medicines lie to their targets in the body. The new technique may be a routine tool in drug development.

The new approach, called CATCH, attaches fluorescent tags to pharmaceutical molecules and employs chemical methods to improve the fluorescent signal, according to a research conducted inCellon April 27, 2022. The researchers identified several different experimental drugs, revealing that the drug molecules hit their targets.

This approach should let us, for the first time, see relatively easily why one medicine is more effective than another, or why one has a specific side effect while another fails, according to study senior authorLi Ye, PhD, who is an assistant professor of neuroscience at Scripps Research and The Abide-Vividion Chair in Chemistry and Chemical Biology.

Zhengyuan Pang, the first author of the research, is a graduate student in the Ye lab. The study also included a close collaboration with the laboratory ofBen Cravatt, PhD, and Gilula''s research chair.

According to Ye, the unique environment at Scripps Research, in which biologists work routinely with chemists, has made the development of this technique possible.

Understanding where drugs bind their targets to exert their therapeutic effects and side effects is a vital component of the drug development process. However, drug interactions often involve relatively limited quantities of drug concentration involving whole organs.

The CATCH technique involves the insertion of tiny chemical handles into drug molecules. These distinct chemical handles do not react with anything else in the body, but they also permit the addition of fluorescent tags after the drug molecules have adhered to their targets. In part because human or animal tissue is prone to diffuse and bloating, and the company has combined the tagging technique with a technique that makes tissue relatively transparent.

The researchers refined and evaluated their methods for covalent drugs, which bind irreversibly to their target by forming stable chemical bonds. This irreversibility of binding makes it particularly important to verify that such medications are targeting their intended targets.

The scientists first discovered several covalent inhibitors of an enzyme in the brain called fatty acid amide hydrolase (FAAH). FAAH inhibitors have the effect of increasing concentrations of cannabinoid molecules, including the bliss molecule anandamide, and are being investigated as therapies for pain and mood disorders. They were able to see, at a single-cell level, where these inhibitors targeted small quantities of mouse brain tissue and could easily distinguish their various patterns of target engagement.

In one experiment, they discovered that an experimental FAAH inhibitor called BIA-10-2474, which resulted in one death and several injuries in a clinical trial in France in 2016, engages unknown targets in mice even when the mice do not have the FAAH enzyme, giving an indication of the source of the inhibitors'' toxicity.

Scientists studied how they could combine drug-target imaging with distinct fluorescent-tagging techniques to reveal the cell types to which a drug binds. They also discovered that drugs-target interactions in different neurons might be significant in scale. Finally, they could see how modestly different doses of a drug often positively affect the degree of target engagement in different brain areas.

Ye believes that the proof-of-principle study is just the beginning. Several individuals and their organizations anticipate to develop CATCH for use on larger tissue samples, possibly whole mice. On the whole, Ye believes the new approach will be a foundation for drug discovery but even for basic biology.

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