Drug-Quadruplex Interactions Revealed

A newly obtained X-ray crystal structure shows how the anticancer agent BRACO-19 interacts with its molecular targets, which are human quadruplexes—guanine-rich DNA assemblies of highly defined structure found at chromosome ends (J. Am. Chem. Soc., DOI: 10.1021/ja8016973). The structure reported by the University of London's Stephen Neidle and coworkers could help scientists redesign BRACO-19 to create analogs with lower toxicity and better anticancer action. The BRACO-19 family of acridine compounds, originally conceived and synthesized by Neidle's group, has been the subject of a drug discovery program at the London-based biotechnology firm Antisoma. In 2006, the company halted preclinical development of BRACO-19 analogs because of adverse side effects, although Antisoma has now restarted the program. The structure, obtained by Neidle, Nancy H. Campbell, Gary N. Parkinson, and Anthony P. Reszka, shows BRACO-19 bound to and sandwiched between two adjacent quadruplexes. The structure reveals that "drug binding to quadruplexes can be altogether more complex than we previously thought," Neidle says. It indicates that loop regions on the periphery of the quadruplexes "play active roles in forming binding pockets for particular drug features," he adds, even though the drug was originally designed to bind quadruplex grooves.