Molecular mechanisms of DNA recognition and function by bioactive compounds

Abstract

Molecular mechanisms of DNA recognition and functional expression by bioactive compounds such as bleomycin, enediyne antibiotics, and zinc finger proteins are an important research subject in the pharmaceutical scientific field. Cleavage of cellular DNA by bleomycin substantially contributes to the antitumor activity of this drug. Some physicochemical data have clearly demonstrated that the bleomycin-iron (II) complex forms a dioxygen adduct species. Of special interest is the fact that the bleomycin-iron complex and cytochrome P450 have a similar dioxygen activation cycle. Probably, the site-specific iron-peroxide species of bleomycin accounts for the action mechanism of selective DNA cleavage by bleomycin. The enediyne antibiotics possess an unprecedented chemical structure, potent anticancer activity, and a fascinating mode of biological action. A new compound, C-1027, consists of a carrier apoprotein and an enediyne chromophore. The high-resolution NMR experiments clarified that novel chromophore interacts with DNA through its benzoxazolinate and aminosugar moiety, and also with apoprotein through the benzoxazolinate and macrocyclic moiety. The results provide a molecular basis for the host-recognition mode, the reaction mechanism, and the drug delivery system of chromoprotein C-1027. In addition, we found unique reactivity of C-1027 chromophore toward a tRNAPhe. RNA as well as DNA might be also a potent biological target of the enediyne antibiotics. On the basis of characteristic DNA binding mode of Cys2His2-type zinc finger motif, artificial zinc finger proteins have been created, and new functions such as DNA cleavage, long sequence binding, and DNA bending are produced. The first artificial His4-type zinc finger protein is also made from Cys→His mutations of the Cys2His2-type transcription factor Sp1. Such novel zinc finger proteins may be useful as a gene therapeutic agent and a tool for genetic engineering.