Chemistry and Chemical Biology: Chemical Diversity, Natural Product Mode of Action, and Organic Synthesis

A solid grounding in the principles of modern chemistry is essential for any multidisciplinary training at the chemistry-biology interface. Therefore, the first research theme focuses on the fundamentals of organic synthesis, the use of chemical and biological diversity in the design and isolation of novel biological tools and the development of natural products as molecular probes of cell biology. The five laboratories listed below take strong multidisciplinary approaches to each of these three areas.

Craig Crews (MCDB) explores novel mechanisms in cell biology using a combination of chemical and biochemical approaches. This strategy has been referred to as “chemical genetics”, whereby biologically active natural products are used as molecular proves for the exploration of cell biology.

Jonathan Ellman (Chemistry/Pharmacology) develops small molecule tools for the study of enzyme function in cells and animals. New fragment based strategies based upon substrate turnover have in particular been developed to obtain potent, selective and pharmacology active small molecule enzyme inhibitors, including for a number of proteases and phosphatases.

Stavroula Hatzios (MCDB) studies proteins that dynamically shape molecular interactions between bacterial and host cells in gastrointestinal infections. Her lab uses quantitative chemical proteomics to selectively identify proteins that are active in complex infection models and determine how infection-associated environmental cues alter their biochemical activity, with the aim of uncovering biochemical pathways that contribute to diseases like stomach cancer and cholera.

Seth Herzon (Chemistry) studies the synthesis and biological properties of complex natural products.  Our syntheses are designed to enable comprehensive investigation of the relationship between natural product structure and biological function.  Based on these studies, simplified synthetic molecules resembling the native natural products are designed.  In some cases, these synthetic molecules are used to probe the molecular mechanisms underlying the biological effects of of our targets.  Alternatively, selected agents are evaluated in preclinical settings, with the ultimate goal of developing new treatments for human illnesses, including cancers and neurodegenerative diseases.

Scott J. Miller (Chemistry) studies complex molecule synthesis as one of the key disciplines of modern chemical research. The development of new methods for the synthesis and derivatization of such structures is a multi-dimensional activity involving reaction design, development and application. Research in our group focuses on each of these aspects of chemical synthesis. Utilizing the architecture and design principles presented by biologically relevant structures and processes, we seek to discover new reactions and to apply new principles to the selective synthesis of complex molecules.

Alanna Schepartz (MCDB) research interests also include novel protein design . Her lab explores a general strategy that is referred to as “protein grafting” for the design of folded, miniature proteins that bind receptors (other proteins or DNA) that themselves bind a-helices. The goal is to understand how to balance the requirements of folding and recognition to generate the smallest possible molecule that retains biological activity.

David Spiegel (Chemistry) develops novel chemical methods to enable the synthesis of a variety of complex molecular targets, including natural products. However, unlike traditional synthetic research programs, these synthetic materials will be used to study the molecular mechanisms that underlie human disease processes (e.g., cancer, Alzheimer’s disease, and diabetes) as well as to develop novel therapeutic approaches to these conditions.

Elsa Yan (Chemistry) studies G protein-coupled receptors (GPCRs). GPCRs belong to the largest gene family in the human genome. They are important drug targets. The Yan group develop methods of using Nanodiscs to purify GPCRs in lipid membrane environments and using unnatural amino acid mutagenesis to label GPCRs with spectroscopic probes. These methods enable molecular studies of GPCRs with biophysical spectroscopy. These studies reveal the activation mechanism of GPCRs, providing insight into rational drug design targeting GPCRs.