| COMMENTS |
Left-handed DNA Finally Gets Some Recognition Stu Borman A scientific team has achieved a long-sought advance in the search for compounds capable of recognizing and modifying DNA on the basis of its shape--as opposed to its sequence, the more commonly used basis for DNA binding and manipulation. The group shows that WP900, the enantiomer of the anticancer natural product daunorubicin, binds selectively to a left-handed (Z-DNA) form of a synthetic DNA polynucleotide. The researchers also demonstrate that the newly synthesized enantiomer can be used in conjunction with daunorubicin--which was already known to recognize right-handed DNA (B-DNA)--to interconvert the polynucleotide back and forth between its left- and right-handed forms. The findings could lead to the rational design of drugs for diseases such as cancer in which altered forms of DNA may play a causative role. In a commentary scheduled to appear in the Proceedings of the National Academy of Sciences USA, pharmacology professor Michael J. Waring of the University of Cambridge notes that the group's results are "of classic significance." The work was carried out by biochemistry professor Jonathan B. Chaires of the University of Mississippi Medical Center, Jackson; professor of medicinal chemistry Waldemar Priebe of the University of Texas M.D. Anderson Cancer Center, Houston; assistant professor of medicine John O. Trent of the University of Louisville; and coworkers [Proc. Natl. Acad. Sci. USA, published Oct. 10, Early Edition, http://www.pnas.org/papbyrecent. shtml]. The study was based on speculation by Chaires, Priebe, and coworkers that daunorubicin's enantiomer might bind DNA of opposite handedness from B-DNA. Priebe and postdoc Izabela Fokt first designed and carried out a total synthesis of WP900, an arduous process that required 33 synthetic steps. Although B- and Z-DNA are not mirror images of each other, Chaires and postdoc Xiaogang Qu found that WP900 bound Z-DNA selectively. Trent aided the effort by developing a predictive molecular model for the binding of WP900 to Z-DNA. "A striking result in our study is that in addition to selectively recognizing particular DNA conformations, daunorubicin and its enantiomer can actively convert DNA to the conformation that provides the preferred binding site for each enantiomer," Chaires tells C&EN. "No chiral complex has shown such an activity." Most agents known to recognize DNA shape are chiral metal complexes. In 1976, physical chemistry professor Bengt Nordén and a coworker at Chalmers University of Technology, Göteborg, Sweden, first reported the selective binding of a tris(dipyridyl)Fe(II) complex to B-DNA. And chemistry professor Jacqueline K. Barton of California Institute of Technology has discovered a variety of chiral metal complexes with selective affinity for B-DNA. Small organic molecules that show enantiomeric selectivity for B-DNA have also been identified by chemistry professor Samuel J. Danishefsky of Memorial Sloan-Kettering Cancer Center and Columbia University and his coworkers and independently by the group of Dinshaw J. Patel, head of Memorial Sloan-Kettering's Nucleic Acid & Protein Structure Laboratory. "This is not the first time that a stereoselective ligand capable of binding to Z-DNA has been described," Waring notes of the new study, "but it does seem to be the first unambiguous demonstration of true selectivity for left-handed DNA over right-handed DNA. . . . The binding constants are not enormous, but they are sufficient to nudge [interconversion of] the polymer in one direction or the other." |
| UPDATE | 10.00 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
|
Want more information ? Interested in the hidden information ? Click here and do your request. |