Light-controlled DNA binding of bisbenzamidines

Biological systems are characterized by a level of spatial and temporal organization that often lies beyond the grasp of present day methods. Light-modulated bioreagents, including analogs of low molecular weight compounds, peptides, proteins, and nucleic acids, represent a compelling strategy to probe, perturb, or sample biological phenomena with the requisite control to address many of these organizational complexities. Although this technology has created considerable excitement in the chemical community, its application to biological questions has been relatively limited. We describe the challenges associated with the design, synthesis, and use of light-responsive bioreagents; the scope and limitations associated with the instrumentation required for their application; and recent chemical and biological advances in this field.

Diamidines, and pentamidine in particular, have a long history as valuable chemotherapeutic agents against infectious disease. Their selectivity is due mostly to selective accumulation by the pathogen, rather than the host cell; and acquired resistance is frequently the result of changes in transmembrane transport of the drug. Here, recent progress in elucidating the mechanisms of diamidine transport in three important protozoan pathogens, Trypanosoma brucei, Leishmania and Plasmodium falciparum, is reviewed, and the implications for drug resistance are discussed.

Over the last four decades, intense research has focused on the effects of small organic compounds that noncovalently bind to nucleic acids. These interactions have been shown to disrupt replication and/or transcription culminating in cellular death. Accordingly, DNA binding compounds have potential applications as anti-cancer and anti-viral agents. This report provides an overview of the different DNA-binding modes with an emphasis on DNA groove specificity for the groove-binding and intercalation modes. While most DNA-interacting agents selectively bind to DNA by either groove binding or intercalation, some compounds can exhibit both binding modes. The binding mode with the most favorable free energy for complex formation depends on the DNA sequence and structural features of the bound ligand.