Click Chemistry Yields Potent and Specific Serine Hydrolase Inhibitors

Drug developers have used the principles of "Click Chemistry" to create a series of low molecular weight inhibitors that selectively block the activity of a large and diverse group of enzymes known as serine hydrolases.

Serine hydrolases are a diverse enzyme class representing approximately 1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. In the current study, investigators at the Scripps Research Institute (La Jolla, CA, USA) applied the principles of "Click Chemistry" to the development of serine hydrolase inhibitors.

"Click Chemistry" is a term that was introduced by K. B. Sharpless in 2001 to describe reactions that are high yielding, wide in scope, create only byproducts that can be removed without chromatography, are stereospecific, simple to perform, and can be conducted in easily removable or benign solvents. This concept was developed in parallel with the interest within the pharmaceutical, materials, and other industries in capabilities for generating large libraries of compounds for screening in drug discovery research.

In a paper published in the May 15, 2011, online edition of the journal Nature Chemical Biology the investigators described the synthesis of a series of 1,2,3-triazole ureas, which were powerful serine hydrolase inhibitors that showed negligible cross-reactivity with other protein classes.

While most of the enzyme-inhibition tests described in the paper were conducted in mouse cell cultures, one of the group's inhibitor compounds, AA74-1, was tested in an animal model. Results revealed that the compound potently blocked the activity of its target serine hydrolase, acyl-peptide hydrolase, or APEH, without significantly affecting other enzymes.

"There are more than 200 serine hydrolases in human cells, but for most we have lacked chemical inhibitors of their activity," said senior author Dr. Benjamin F. Cravatt III, professor of chemical physiology at the Scripps Research Institute, "so we have had only a limited ability to study them in the lab or to block them to treat medical conditions. This new research allows us to greatly expand our list of these inhibitors. We are also using the techniques described in this paper to try to systematically generate more of these inhibitor compounds. We see these compounds as basic tools that enable us to determine the roles of serine hydrolases in health and disease. As we understand these enzyme roles better, we expect that some of their inhibitors could become the bases for medicines."

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