Nobel Centennial Symposia
"Frontiers of Molecular Science"

December 4-7, 2001
Friiberghs Manor, Örsundsbro and Stockholm University

Regulation of Gene Expression by Synthetic DNA Binding Ligands

by Peter B. Dervan
Division of Chemistry and Chemical Engineering California Institute of Technology, Pasadena, CA 91125, USA

In the 21st century, mapping and sequencing the genetic blueprint in humans, mice, zebrafish, (and other model organisms) will create challenges and opportunities at the interface of chemistry and biology. An understanding of the function of each of the 40,000 genes in humans, and the biological circuitry that controls these genes will in part be driven by new analytical methods and new technologies from the world of chemistry. Small molecules that specifically bind at subnanomolar concentrations to predetermined DNA sequences in the human genome would be useful tools in biology and potentially in human medicine. For example, many cellular events that lead to cancer and the progression of human disease represent aberrant gene expression and transcription. The search for a set of simple chemical principles wherein synthetic ligands could be designed to read the DNA double helix will be described.¹ Pairing rules have been developed to control rationally the DNA sequence specificity of minor-groove-binding polyamides containing three aromatic ring amino acids, hydroxypyrrole (Hp), imidazole (Im), and pyrrole (Py). Hairpin polyamides achieve affinities and specificities comparable to DNA-binding proteins. This chemical approach to DNA recognition could provide an underpinning for the design of cell-permeable molecules for the control of gene-specific regulation in vivo. The technical hurdles remaining to reprogram gene expression by small molecules and the possibility of "transcription therapy" will be discussed.

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(1) Molecular Recognition of DNA by Small Molecules. P. B. Dervan, Bioorg. & Med. Chem., 9, 2215 (2001).