CAREER: Biosynthesis and Evolution of Pharmaceutical Leads

University Of Colorado At Boulder, Boulder CO

Investigators

Abstract

Many drugs are molecules that target proteins. This project will establish an approach to create leads for new drugs by identifying molecules that will inhibit the target protein, then identifying enzymes that can produce this inhibitor. The initial targets will be relevant to the treatment of diabetes, obesity, and cancer. The technology developed in this project will accelerate the rate and lower the cost of drug development by enabling the rapid discovery and biological synthesis of the drug molecule. A summer biotechnology training program for high school students currently underrepresented in STEM will contribute to the development of a highly-skilled workforce, and a core facility for teaching and research on inhibitor identification and production will further enhance drug development. This project represents a significant departure from contemporary efforts to use microbial systems for the synthesis of clinically approved drugs and their precursors. We will carry out a detailed study of the molecular basis and thermodynamic origin of affinity and activity. The structure-affinity and structure-activity relationships formulated will be exploited to develop experimental and computational methods for the evolution of high-affinity leads. This will result in a general framework for assessing the structural limits of functional compatibility between enzymes (i.e., their ability to synthesize, functionalize, and/or bind similar molecules), and for working within those limits to build new inhibitors. The ultimate goal is to validate the approach of screening metabolic pathways to produce molecules with targeted biological activities rather than targeted structures. If successful, this project could yield a general and low-cost approach for using synthetic biology to replace synthetic chemistry in lead development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.