For several years now, chemists and biologists have been intrigued with DNA “antisense” technology. For example, chemists have designed modified RNAs which, through complementary base-pairing, can target specific regions of viral RNA. Such molecules are of interest as potential antiviral drugs. Similarly, it is possible to design oligonucleotides that are complementary to a target region of DNA. Through triple-helix formation these oligonucleotides are able to interfere with the expression of the DNA. The problems encountered with this technology have led chemists to look for other types of molecules that could be designed to bind to DNA. The inspiration for this idea comes from nature itself: a number of proteins are known to bind specifically to certain DNA sequences–restriction endonucleases and repressor proteins, to name two. Such compounds could in principle be directed at will to certain DNA sequences, in order to suppress the expression of target genes. This would have potential for antiviral therapy, since it may be possible to design synthetic compounds that would specifically target viral DNA, including that produced from RNA viruses.

Chemists at the California Institute of Technology, led by Peter Dervan, recently announced a significant advance in the study of DNA recognition by showing that they could prepare oligomers of heterocyclic amides that recognize certain DNA sequences by binding to the minor groove of DNA (1-3).

Dervan’s work started with three synthetic amino acid subunits:

Various combinations of these three subunits were fabricated into hairpin-shaped oligomeric amides. An example is the compound, ImImPyPy-g-ImHpPyPy-b-Dp, in which three of these subunits are joined with three straight-chain liking units–g, b, and Dp. Its structural formula is shown below:

ImImPyPy-g-ImHpPyPy-b-Dp

This molecule can be represented schematically as follows:

Schematic views of hairpin oligomer

The structure of DNA consists two strands of polynucleotides, each of which has a backbone of alternating phosphate and sugar groups, to which are attached the bases that transmit the genetic code. The two polynucleotide strands are twisted together like a rope, in a structure known as an a helix. The geometry of the individual components of the double-stranded helix is such that two grooves, called the major groove and the minor groove, are formed along its outside surface. The hairpin-shaped synthetic polyamide molecules fit within the minor groove of DNA, where they can interact with the edges of the various base pairs, with the portion of the bases not already involved in base-pairing. The following figure shows the DNA structure and how a typical hairpin oligomer lies in the minor groove.

A synthetic hairpin oligomer lies in the minor groove of DNA

The minor-groove interactions can be schematically represented in the following way:

Each base pair in the minor groove requires a specific pair of amide subunits. For example, the A-T base pair requires a Py-Hp amide pair (green box); a C-G pair requires a Py-Im amide pair. The authors propose that the attractive interactions involve very precisely positioned hydrogen bonds.

The key to the success of this work was the discovery that Hp (a hydroxypyrrole derivative) could be used to differentiate A-T pairs from T-A pairs. The authors are not certain about the molecular basis for this differentiation. They showed, using a series of analogs, that specificity was generated not only by differential attractions of DNA to the appropriate base pairs, but also by differential repulsions. Molecules large enough to target about seventeen base pairs will be necessary for the exquisite specificity needed to recognize a single DNA site.

Unanswered questions abound: What is the effect of nearest-neighbor interactions? For example, how is the A-T specificity of Py-Hp pairs affected by the identity of neighboring base pairs? Can molecules like these oligomers gain entry into cells? Whether this strategy for producing anti-DNA molecules can become of practical significance for drug development remains to be seen.

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