My laboratory is interested in discovering new ways to treat acute and chronic diseases. There are three main projects in the lab.

The first project is aimed at finding new targets for drug discovery. In the traditional drug discovery process, researchers select a target and then attempt to find appropriate drugs to attack the target. We have developed a novel chemical genomic approach called PARIT (Xiong & Scott, Meth. Mol. Biol. (2014) 1088:81-96) that enables rapid discovery of druggable targets in disease pathways of interest. In our approach, collections of diseased cells are given genetic instructions to make molecules in such a way that each cell gets a different set of instructions. The approach is a bit like a lottery: cells that get instructions to make molecules that cure the disease, or selectively kill cells carrying it, can be identified using powerful genetic selection and screening methods that we develop in the laboratory. Molecular "hits" that emerge from the selection/screening process are produced and studied in detail to determine the physiological target and understand how the hit molecule modulates the target's biochemical function. The end result is identification of the best targets for drug development, and molecules that can serve as lead compounds or even drugs.

The second project is focused on developing new drugs for the treatment of tuberculosis. Fully one third of the world’s population (> 2 billion people) is currently infected with Mycobacterium tuberculosis (Mtb), nearly ten million new infections occur every year and more than one million people die from the disease annually. To make this terrible situation even worse, multiple- and extensively drug resistant strains of Mtb are becoming more prevalent (~ 5% of all new infections – nearly 500,000 per year – are drug resistant). We have recently elucidated the detailed kinetic mechanism for a unique target in the mycobacterial respiration system, type II NADH dehydrogenase (NDH-2), which accounts for the physiological activity of this essential enzyme, uncovers a novel, druggable site in the enzyme and rationalizes the antimycobacterial activity of a largely forgotten class of antibiotics (Yano, et al., in press). This work has stimulated a new trial by the Global Alliance for Tuberculosis Drug Development aimed at reintroducing these drugs into clinical practice, and will be followed up by a multi-investigator effort to generate and characterize second-generation derivatives guided by our mechanistic studies.

The newest project in the lab aims to develop next-generation therapeutics for the treatment of asthma and chronic obstructive pulmonary disease (COPD), which result from airway constriction. Current therapies for asthma and COPD rely on long-acting beta-agonists, which activate the β-2 adrenergic receptor (β2AR) and promote relaxation via the downstream cAMP-dependent signaling pathway. However, the therapeutic benefit of these agents diminishes with prolonged treatment due to tolerance mediated by receptor desensitization. We are interested in developing biased β2AR agonists and/or inhibitors of the desensitization pathway in order to prolong cAMP-mediated relaxation of airway smooth muscle and thereby improve disease management. We are pursuing a multi-pronged discovery effort, including high-throughput screening of small molecule libraries, virtual screening and expression-based chemical genetics in order to achieve this objective.