Bugs on Drugs Go GAGAA

Replacement of C-H in pyrrole with N: in imidazole allows for the formation of a hydrogen bond with this Seattle, Washington 98109 guanidine NH 2. In the context of a side-by-side dimer, a G/C base pair is contacted by an imidazole (Im) touching guanine and a pyrrole (Py) touching cytosine. For exam-Sometimes science fact resembles science fantasy, ple, GTA/CAT can be recognized by ImPyPy/PyPyPy. more suitable for the supermarket checkout display than Extending beyond a few base pairs requires spacers, the research library. A case in point is an article in the because the polyamides become strained when follow-November issue of Molecular Cell that could pass for ing the DNA trajectory. A ␤-alanine (␤) is generally used the subject of a B-grade sci-fi movie: Some unfortunate as a spacer, because a ␤ can take the place of a pyrrole, creature ingests a compound cooked up in the labora-allowing recognition of longer sequences. To obtain di-tory and undergoes a profound transformation. Implau-meric compounds with increased specificity and affinity, sible as such a scenario may seem, Laemmli's group a linker connects the two side-by-side monomers to reports that when certain Drosophila larvae are fed a form a hairpin. sequence-specific DNA binding compound they un-The subnanomolar affinities for specific short se-dergo homeotic transformations (Janssen et al., 2000a). quences achieved in these studies encouraged in vivo These transformations involve targeting of the com-experiments. Transcription factor binding sites provide pound to the minor groove of a GAGAA-rich repetitive attractive targets in cases where minor-groove binding element, and evidently mimic a mutation in the gene would interfere with function. For example, TFIIIA has 9 encoding the GAGA factor (GAF) DNA binding regulatory zinc fingers, some of which contact the minor groove. protein. This astonishing result not only has implications for understanding repetitive sequences, heterochroma-tin, and DNA binding interactions, but also provides a new class of cytological tools. What's more, the strange fate of bugs on drugs represents another milestone on the way to therapeutic drugs that bind DNA in the minor groove. Minor-Groove Binding Compounds This breakthrough by Laemmli's group builds upon extensive studies of synthetic compounds that are mod-eled on the naturally occurring drugs distamycin and netropsin. These are polyamides containing aromatic pyrrole rings, which fit snugly into the narrow minor groove of A/T-rich DNA (Figure 1, top). Over the past decade, a series of reports, principally from the Dervan laboratory, have succeeded in increasing …