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Building a new toolbox
BUFFALO, N.Y.—A recent grant will support chemists at the University at Buffalo (UB) in their work to develop intracellular biochemical tools that can provide an inside look at how exactly pharmaceuticals impact the inner workings of cells during treatment.
“Our project utilizes chemistry as a research tool to study biological problems inside living cells,” said lead scientist Dr. Qing Lin, professor of chemistry in the UB College of Arts and Sciences. “Even when a drug works in treating disease, we often don’t understand the details of how it does its job. The tools we are developing will hopefully help to fill this gap in knowledge.”
The grant in question provides $2 million from the National Institute of General Medical Sciences, part of the U.S. Institutes of Health, and is expected to help fund development and testing of the biochemical tools.
Lin’s lab, as noted on the UB website, is focused on research that “aims to develop and apply new chemical tools and principles to solve biological problems that are difficult to solve, if not impossible, by standard biological techniques. A central theme of our research is to harness the power of organic reactions to study protein dynamics, function and protein-protein interactions and their assembly in living organisms.”
Lin is particularly interested in cellular receptors and bioorthogonal chemistry.
“Compared with the noncovalent binding-based approach, bioorthogonal chemistry relies upon a specific, covalent attachment of a probe molecule to the biomolecule(s) of interest,” as noted on his laboratory’s website. “Over the past few years, we have developed several bioorthogonal reactions, most notably, a photoinduced tetrazole-alkene cycloaddition reaction (“photoclick chemistry”) and a palladium-mediated cross-coupling reaction, for protein labeling in vitro and in vivo. Our current efforts are geared toward the application of bioorthogonal chemistry to understand the conformational dynamics of the class B G-protein coupled receptors in living cells.”
Recent work includes the development of tools to study how these cellular receptors change shape once activated, and how molecules within the cells respond upon activation. Lin’s lab is engineering fluorescent probes to attach to cellular receptors and monitor change, as well as genetically engineered cellular receptors that can “trap” targeted molecules to shed light on which molecules inside of cells interact with activated receptors on the surface of a cell. Related efforts were detailed in a paper published in November in CHIMIA International Journal for Chemistry titled “Recent Developments of Photo-Cross-Linkers as Tools for Biomedical Research.”
The authors, including Lin, report that “Photo-cross-linkers are invaluable tools for identifying drug targets and off-targets as well as probing the binding sites in medicinal chemistry and chemical biology. In this review, we summarize recent development of the ligand-based and genetically encoded photo-cross-linkers and their use in biological system. In particular, we highlight our discovery of 2-aryl-5-carboxytetrazole (ACT) as a novel class of photo-cross-linkers and their successful applications in drug target identification as well as identifying transient protein–protein interaction complexes in mammalian cells.”
Within the auspices of the National Institute of General Medical Sciences grant, Lin and his lab are specifically focusing on class B G protein-coupled receptors (GPCRs) that are implicated in diseases such as diabetes, depression and osteoporosis.
“Our tools will enable scientists to monitor what happens inside a cell when a receptor is activated in real time,” Lin said. “This is very valuable, because different molecules can activate the same receptor in different ways and trigger different downstream signaling events within cells, which may produce discrete physiological responses.”
This isn’t the first funding Lin has received for his work from the NIH. Last summer, Transira Therapeutics LLC—a UB spinoff founded by Lin—received a $224,000 Phase 1 Small Business Innovation Research award from the National Institute of Diabetes and Digestive and Kidney Diseases to support the development of a hormone-based drug that could help control blood sugar and support weight loss in patients with type 2 diabetes. The goal is a therapy that could be injected once-weekly, and UB researchers will work in collaboration with the California Institute for Biomedical Research (Calibr).