Approaches Toward the Design of Sequence-Specific Drugs for DNA

This chapter describes strategies that could lead to the development of drugs that are potentially useful as modulators of gene expression and directors of recombinogenic events in human cells. However, numerous problems need to be solved before this objective can be reached. Only scant information is available on the rules for sequence specificity and it is not clear that nonintercalating agents that read DNA by secondary sequence mechanisms may be capable of sufficient discrimination between target and nontarget sequences. If the human genome is the target for the sequence-selective agent, then it is important to consider the size of a unique target and by implication, the size of the sequence-specific probe to be designed. Using a conditional probability approach, a distinguishable sequence has a binding site size of 15 to 16 base pairs. This is a formidable objective when the size of the potential drug (1900-2500 daltons) and the problems this may present in formulation and cellular uptake are taken into account. Nevertheless, physical and biochemical techniques are now available to extract the type of sophisticated information needed to solve some of these problems. It is, therefore, with cautious optimism that medicinal chemists can now embark on the research projects in this area. As molecular biologists unravel the mechanisms controlling genetically mediated events, such as recombination, gene amplification, and rearrangements, it may be possible to intervene or even direct these events, using low molecular weight sequence specific probes.