Butting in on DNA replication is one way of treating diseases such as cancer. In the January issue of Nature Structural Biology, Aymami and colleagues describe a new type of drug interaction with DNA that is revealed by the crystal structure of DNA bound to cryptolepine, an alkaloid extract of Cryptolepis sanguinolenta. Although extracts of cryptolepine have already been used in Central and Western Africa for the treatment of malaria, the novel way in which cryptolepine interferes with DNA processing might lead the way to new antiprotozoal and anticancer drugs.

Many drugs work by DNA intercalation, a specific mode of DNA binding in which a molecule lodges itself between bases within the DNA helix. Intercalators therefore interrupt transcription, replication and the topoisomerase activity that regulates DNA topology. Previously, two main kinds of DNA–drug intercalation have been observed. Perpendicular intercalation is typified by long, fused ring molecules that penetrate the bases, so that they lie perpendicular to the base-pair hydrogen bonds, as shown by the drugs doxorubicin and daunomycin. In parallel base-stacking intercalation, drugs such as actinomycin and acridine lie parallel to the base-pair hydrogen bonds with their aromatic rings stacked into the DNA bases. All these intercalators position themselves between alternating pyrimidine–purine sites.

Cryptolepine binds tightly to DNA, but although the crystal structure of the cryptolepine–DNA complex shows that the drug intercalates in a parallel base-stacking fashion, it lies between non-alternating pyrimidines — cytosines — rather than between pyrimidine–purine contacts. This is the first evidence for such intercalation between non-alternating DNA bases and has important implications for drug design because of the asymmetric way in which cryptolepine binds. Cryptolepine contains four ring structures; at one end of the molecule, an aromatic six-membered ring stacks between the two cytosines, whereas a fused aromatic double six-membered ring at the other end stacks between the two guanines. The inner ring of the double six-membered ring is positively charged and penetrates deeply into the the helical stack, forming strong hydrophobic interactions with the base pairs and positioning its centre of mass as close to the helix axis as possible, where the negative electrostatic potential of the DNA is greatest. In this way, both its hydrophobic and electrostatic interactions are maximized. Importantly, the solved drug–DNA complex reveals that hydrogen bonds contribute little to the stability of the complex. These intercalating properties of cryptolepine might open the door to new strategies for designing drugs to target a wide range of diseases that are dependent on DNA replication.