Drugs that bind to nucleic acids, blocking transcription and replication, are important in the treatment of cancer and AIDS-related diseases. Drugs of clinical importance act by several mechanisms: alkylating agents, such as nitrogen mustard and nitrosoureas, and platinum coordination complexes, such as cisplatin, form cross-links in DNA; anthracycline antibiotics, such as daunorubicin and doxorubicin, intercalate in double-stranded DNA; iron-chelating antibiotics, such as bleomycin, fragment DNA; and groove-binding drugs, such as pentamidine, bind in the minor groove of DNA. These drugs show limited sequence specificity and bind to many sites in a typical genome, leading to harmful side effects. Recently, the search for new chemotherapeutic agents has shifted to molecules designed to target a given DNA sequence in a pathogenic organism or neoplastic cell. Polyamide molecules such as netropsin, distamycin, and their imidazole-containing synthetic derivatives, known as lexitropsins, can bind DNA in a sequence-specific manner in a 2:1 polyamide–DNA stoichiometry (refs. 1–3 and M. L. Kopka, D.S.G., and R.E.D., unpublished work). In this mode, the two molecules bind side-by-side, enabling each molecule to recognize its own strand of DNA.
