This award in the Chemistry of Life Processes (CLP) program supports work by Professor Danith H. Ly at Carnegie Mellon University to carry out fundamental studies on DNA recognition. The work is focused on the design and development of a particular class of synthetic reagents, called gamma-peptide nucleic acid acids, for recognition of double helical B-DNA through direct Watson-Crick base-pairings. Molecules that can be designed to bind sequence-specifically to double-stranded B-DNA are of considerable interest in biology, biotechnology and medicine. Such molecules could be developed into a number of applications, from molecular tools for probing sequence information and regulation of gene expression in our attempts to understand the molecular basis of life, to therapeutic and diagnostic reagents for the treatment and detection genetic diseases.

In addition to their applications in biology, biotechnology and medicine, such molecules could be used in a number of other disciplines including drug discovery and molecular self-assembly, owing to their tight and specific binding properties along with the ease and flexibility of synthesis. The work will have a direct impact on how nucleic acid sequence information is detected, how gene expression is regulated, and how molecules are organized and assembled. This dual-research program, combining research with hands-on training, will provide students and research associates with a unique skill set essential for their future career in graduate schools as well as in industry, by providing strong scientific training and by exposing them to cutting-edge research early in their educational career.

Project Report

The overall goal of this research program was to develop a nucleic acid platform for recognition of double helical DNA (and RNA) based on the digital rules of Watson-Crick base-pairing. The work entailed the design, synthesis, and molecular characterization of a new class of conformationally-preorganized and biocompatible g-peptide nucleic acids (gPNAs). gPNAs differ from all other classes of nucleic acid mimics that have been developed to date in that they can be designed to bind to any sequence of double-stranded DNA (or RNA) at the physiological temperature and ionic strengths via strand invasion, with the recognition occurring through directional hydrogen-bonding interactions. This unique feature has enabled the development of several applications in biology and biotechnology, including telomere painting, electronic barcoding, gene regulation, and gene correction, as well as potential treatments for genetic and infectious diseases. In addition to the development of such enabling technologies, the research has served as a training ground for a large number of high school, undergraduate, and graduate students; and postdoctoral associates in synthetic, physical organic, analytical, and biophysical chemistry, as well as in molecular and cellular biology. Implementation of this research program has strengthened the PI’s ongoing effort to build a chemical biology program at Carnegie Mellon University that promotes rigorous undergraduate research training and fosters interest in science among K-12 students and teachers in the Greater Pennsylvania area. By providing students with strong scientific training and by exposing them to cutting-edge research early in their educational career, this interdisciplinary program has given them a unique skill set that is essential for their future career in either graduate school or the industry.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Colby Foss
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Carnegie-Mellon University
United States
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