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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 study was based on speculation by authors. that daunorubicin's enantiomer might bind DNA of opposite handedness from B-DNA. Authors 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, authors found that WP900 bound Z-DNA selectively. Authors 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. "No chiral complex has shown such an activity." WP900 also turns out to be cytotoxic to cancer cells, making it a possible lead compound for Z-DNA-targeted anticancer agents. In future work, authors plan to study WP900's mechanism of action and create modified versions that may have higher binding affinity and selectivity for Z-DNA |
| UPDATE | 10.00 |
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