kiesslin

Our group develops and implements synthetic methods to access biologically-active compounds for hypothesis-driven and discovery-driven research. This important foundation of our program offers chemically-oriented researchers new opportunities to develop and apply their synthetic skills. Biochemically- and biologically-oriented researchers benefit from access to unique biologically active ligands. Some representative questions that drive our interdisciplinary research program follow.

What are the biological roles of carbohydrates?
Carbohydrates can influence protein stability and protein trafficking; they also also are important in recognition and can act as signals. Illuminating the biological roles of carbohydrates stands as a major scientific forefront. Chemical synthesis is uniquely poised to address this challenge. In our initial forays into the array, we focused on synthesizing carbohydrates and glycoconjugates to explore their roles. These studies led to new discoveries about how sulfation influences carbohydrate recognition and the role of carbohydrate-binding proteins in embryo implantation. More recently, we are focused on finding non-carbohydrate inhibitors. These compounds can be used to block important protein-carbohydrate interactions or to inhibit specific carbohydrate biosynthetic enzymes. Some examples of the kinds of targets are shown in the Figure.

Can we exploit carbohydrate recognition for new purposes?
We used the properties of carbohydrate recognition to devise a strategy to mediate selective killing of tumor cells. Our approach exploits the features of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. We used a chemically-synthesized, small‑molecule composed of two distinct motifs: (1) a ligand that binds tightly (K_d ~ 10^-9 M) to a_vb₃ integrins, and (2) a carbohydrate (galactosyl-a(1-3)galactose or a‑Gal epitope), which is recognized by human anti-a‑galactosyl antibodies (anti-Gal). Importantly, anti-Gal antibodies are recruited when the bifunctional conjugate decorates a tumor cell possessing a high level of the target receptor (the a_vb₃ integrin); anti-Gal then triggers cell killing. Tumor cell lines with high levels of the integrin receptor are killed (Figure). Our results have implications for the treatment of cancer and other diseases.

How do cells detect and respond to stimuli in the environment?
The view from the surface of a cell reveals a complex milieu composed of membrane-associated proteins, lipids and carbohydrates. This surface of molecules is a remarkable conduit of information. The molecules on the surface have the critical role of reporting to the interior on extracellular conditions (e.g., presence of nutrients or toxins), so that the cell can respond appropriately. We have been designing chemical probes to understand the mechanisms underlying how molecular signals are processed.