Scripps Research has developed a way to image, across different tissues, and with greater precision than ever before, where drugs are linked to their targets in the body. The new method might become a mainstream tool in drug development.
The CATCH experiment, which was developed by CATCH, has several different experimental drugs, revealing that even within one cell the drug molecules reached their goals.
According to a research senior author, this approach will let us for the first time see relatively easily why one drug is more powerful than another, or why another has a specific side effect while another one does not.
Zhengyuan Pang, the first author of the study, is a graduate student in the Ye lab. The study also involved a close collaboration with Professor Ben Cravatt, PhD, and the Gilula Chair of Chemical Biology at Scripps Research.
The unique environment at Scripps Research, where biologists work tirelessly with chemists, has led to the development of this technique, according to Ye.
Understanding how drugs are binding their targets to exert their therapeutic effects and side effects is a fundamental part of drug development. However, drug-target interaction studies have often involved relatively unpredictable methods, such as bulk analysis of drug-molecule concentration in whole organs.
The CATCH technique involves the insertion of tiny chemical handles into drug molecules. These distinct chemical handles don''t react with anything else in the body, but they also allow the addition of fluorescent tags after the drug molecules have been bound to their targets. Ye and his team combined the tagging technique with a technique that makes tissue more transparent.
In this initial study, researchers refined and evaluated their technique for covalent drugs, which bond 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 meeting their intended goals.
The researchers first analyzed several covalent inhibitors of an enzyme in the brain called fatty acid amide hydrolase (FAAH). FAAH inhibitors have the effect of increasing levels of cannabinoid molecules, including the bliss molecule anandamide, and are being investigated as treatments for pain and mood disorders.
In one experiment, they demonstrated that an experimental FAAH inhibitor called BIA-10-2474, which caused one death and several fatalities in a clinical trial in France in 2016, has employed unknown targets in mice even when the mice lack the FAAH enzymeoffering a clue to the source of the inhibitors'' toxicity.
Researchers used novel therapies to uncover cell types to which a drug binds. They could also distinguish drug-target engagement sites in different neurons. Finally, they could see how modestly different doses of a medication often affect the degree of target engagement in different brain areas.
Ye notes that the proof-of-principle study is just the beginning. He and his team are planning to develop CATCH further for use on thicker tissue samples, ultimately perhaps whole mice. Moreover, they intend to expand the basic approach to more common, non-covalently binding drugs and chemical probes. On the one hand, Ye claims, the new method is a powerful tool for drug discovery but even for basic biology.