Design of synthetic sequence specific DNA binding molecules

Abstract

The design of sequence specific DNA binding molecules has advanced in recent years due, in part, to analytical techniques such as footprinting and affinity cleaving which allow rapid and precise analysis of hundreds of potential DNA binding sites on sequencing gels (Dervan, 1986 ). Nona-N-methylpyrrolecarboxamide, a synthetic analog of the natural product distamycin, binds 11 contiguous base pairs of A,T rich DNA in the minor groove. A synthetic polypeptide, 52 amino acid residues in length and derived from a recombinase protein, binds uniquely 12 base pairs of DNA, most likely in the major and minor groove. The construction of synthetic molecules that bind in the minor and major groove of DNA with incrementally increasing sequence specificity is the first step toward defining a set of rules for the three-dimensional readout of double helical DNA. This may lead to new research tools for use in cancer research, diagnosis of disease states at the level of DNA (oncogenes), and novel chemotherapeutic strategies such as artificial repressors for inactivation of these genes.