Inhibiting disease one enzyme at a time

Enzyme inhibitors are precisely what they sound like: molecules that bind to an enzyme and slow down or stop the chemical reaction promoted by that enzyme. Inhibitors are critical to the study and treatment of a wide range of diseases – halting a specific biological process helps researchers better understand how that process works to promote health or disease. Enzyme inhibitors can control inflammation in arthritis patients, slow cancer progression, or stop bacterial infections.

In Bright Futures Assistant Professor James Van Deventer’s lab at Tufts School of Engineering, researchers are working toward the development of a new class of enzyme inhibitors that inhibit metalloproteinases – a superfamily of enzymes that plays roles in everything from remodeling tissues during human development to catalyzing chemical reactions in disease-causing bacteria. This summer, Van Deventer received a National Institute of General Medical Sciences (NIGMS) R35 Outstanding Investigator Award from the National Institutes of Health (NIH) to further that work.

The ideal enzyme inhibitor has two key qualities: it’s specific to one enzyme, so that it doesn’t interfere with the essential functions performed by closely-related enzymes, and it disrupts that particular enzyme’s function. While those may sound like straightforward qualifications, developing inhibitors that meet both needs is deeply challenging.

Two primary classes of enzyme inhibitors are antibodies and small-molecule chemicals. Antibodies are capable of very specifically recognizing a particular enzyme but rarely disrupt enzyme function, while small molecules successfully disrupt enzymatic function but aren’t usually very specific. Van Deventer wants to develop enzyme inhibitors that would combine the best of both worlds: the single-target specificity of antibodies and the activity-disrupting power of small molecules.

In order to realize potent, specific inhibitors, scientists and engineers need robust tools to discover and test new inhibitors. Researchers in Van Deventer’s lab seek to establish strategies to construct, isolate, and evaluate enzyme inhibitors on the surface of yeast. The goal is to push yeast display, a well-established antibody engineering technology, in new directions by enabling yeast to add chemical building blocks called noncanonical amino acids into antibodies. This would facilitate the introduction of diverse small molecule features into antibodies, greatly expanding the range of chemical functionalities available for engineering antibody-based inhibitors.

In the research funded by this award, Van Deventer plans to continue establishing general strategies for enabling the combination of yeast display and noncanonical amino acid incorporation to serve as an inhibitor discovery platform. A comprehensive platform integrating the complementary capabilities of antibodies and small molecules could provide access to new classes of inhibitors useful for both understanding and treating diseases ranging from infections to cancer.

“What excites me most about this award is that it supports the development of several key elements of a yeast-based inhibitor discovery platform that can be used individually or in combination with one another,” says Van Deventer. “This versatility will enable us to explore many possible strategies for targeting disease-promoting enzymes for which no inhibitors are currently available.”

 This research is funded by an NIGMS National Institutes of Health R35 Outstanding Investigator Award, project number 1R35GM133471-01.