Design of Biofunctional Molecules based on Molecular Recognition

本研究项目的目的是在阐明自然产生的DNA裂解分子的DNA裂解机制的基础上，设计一种针对DNA的新型生物功能分子。天然抗肿瘤抗生素，如博莱霉素、新卡西诺抑素、卡普霉素或双霉素等在特定部位裂解DNA。我们能够利用寡核苷酸作为DNA底物来阐明博莱霉素、新卡宾抑素和卡普里霉素诱导DNA切割的机制。我们还成功地设计了一种独特的低聚物探针，它的靶点有一个自由基时钟。通过使用这种新型齐聚物，我们首次证明了脱氧核糖残基的C-4‘自由基实际上是由活化的博莱霉素作用产生的。序列特异性DNA切割器的设计我们已经成功地设计了几种重要的序列特异性DNA切割器，它们在分子生物学和光生物学中有广泛的应用。其中一个值得注意的DNA裂解是光刺激下特定于-GG的DNA裂解分子。我们还设计了一种实用的DNA裂解氨基酸，它可以结合到DNA结合多肽的所需位置。

The aim of this research project is to design a novel biofuctional molecule targeted to DNA,based on the elucidation of the DNA cleavage mechanisms of naturally occuring DNA-Cleaving molecules.1. Mechanistic Studies on the Action Mechanism of DNA-Cleaving Antitumor AntibioticsNatural antitumor antibiotics such as bleomycin, neocarzinostatin, kaprimycin, or duocarmycins are known to cleavage DNA at specific sites. We are able to elucidate the mechanisms of DNA cleavage induced by bleomycins, neocarzinostatin and kapurimycins by using oligonucleotides as a DNA substrate. We have also succeeded to design a unique oligomer probe which has a radical clock at the target site. By using this novel oligomer, we were able to demonstrate for the first time that C-4' radical of deoxyribose residues is actually generated by the action of activated bleomycins.2. Design of Sequence Specific DNA CleaversWe have succeeded to design several important sequence specefic DNA cleavers which could find wide spread application in molecular biology and photobiology. One of the notable DNA cleavers is the -GG- specific DNA-cleaving molecule upon photostimulation. We also designed a practically useful DNA-cleaving amino acid which can be incorporated into the desired sites of DNA-binding polypeptides.