DNA AS A THERAPEUTIC TARGET FOR THE NEW MILLENIUM: FROM DUPLEX TO QUADRUPLEX

Stephen Neidle

CRC Biomolecular Structure Unit, The Institute of Cancer Research, Surrey SM2 5NG, UK

Double-stranded DNA is the primary target for many of the established anticancer drugs in current clinical use, notably alkylators and intercalating agents. Their mode of action invariably involves interference with a protein-DNA function, typified by inhibition of the initiation of transcription, or the stabilisation of a DNA topoisomerase cleavable complex. However, such drugs are inherently unable to selectively interact with genes involved in cancer processes, and thus their utility remains limited.

There is now a large knowledge base of primary DNA sequence data on many oncogenes, tumour suppressor proteins and oncogenic gene translocations, which together with the rapid pace of the Human Genome Project, means that targeting individual disease genes with gene chemotherapeutic agents will become a real possibility. This can be achieved at several levels of DNA organisation, with structural information providing key insights into the design of sequence and structure-selective agents.

The recognition of particular sequences at the DNA duplex level has been extensively studied by X-ray crystallography. Recent results on the role of groove width and structured solvent will be presented. The formation of triple-stranded DNA with oligonucleotides forming Hoogsteen or reverse-Hoogsteen hydrogen bonds to a target duplex, can be highly sequence-specific; however there are several sequence restrictions to the general applicability of this approach. X-ray crystallography combined with molecular modelling and simulation is providing guidance to further triplex studies. At a still greater level of tertiary organisation, DNA sequences containing repeating G/T telomeric motifs (such as d(TTAGGG)_n in humans), can form four-stranded structures containg guanine quartets. These have been characterised by X-ray crystallography and NMR. Such structures are also potential selective targets for chemotherapeutic intervention.