Platinum Metal Complexes as DNA-Protein Cross-linking Agents

弗吉尼亚联邦大学化学系Nicolas P.Farrell博士由化学部无机化学、生物无机化学和金属有机化学项目支持，探索DNA-蛋白质相互作用的基础化学，涉及铂(或金属)核苷酸和寡核苷酸与锌指蛋白质的相互作用。对影响选择性识别、三元铂-DNA-蛋白质加合物形成和锌排出的因素进行了探讨。被单一铂络合物修饰的寡核苷酸将被用作底物来研究识别和结合位点。初步研究的锌指蛋白将是转录因子Sp1(Cys2His2核心)和修复蛋白XPA。(Cys4核心)。将评估配体交换速率、铂可能进入多肽的可能性、锌排出和构象损失。这种金属交换的基础化学将通过模型铂和含锌络合物的制备和结构表征来研究。通过增强铂碱基和色氨酸之间的圆周率堆积，将用光谱和计算方法研究在基本芳香氨基酸和铂碱基化合物之间选择性识别的可能性。该项目将使人们更深入地了解DNA构象在蛋白质识别中的作用，DNA损伤的性质如何影响下游蛋白质的加工和DNA修复，并最终在体内分离DNA-蛋白质加合物。更广泛的影响将是将本科生和研究生研究人员纳入这些活动。将促进与捷克共和国和以色列的国际合作。这项工作对社会的长期影响将是扩大知识基础；以理性和创新的方式挑战现有概念的现状，并为新药的开发奠定基础。

Dr. Nicolas P. Farrell, Chemistry Department, Virginia Commonwealth University, is supported by the Inorganic, Bioinorganic, and Organometallic Chemistry Program of the Chemistry Division to explore the fundamental chemistry of DNA-protein interactions involving platinated (or metallated) nucleobases and oligonucleotides with zinc finger proteins. The factors affecting selective recognition, ternary Pt-DNA-protein adduct formation, and zinc ejection from the peptide will be explored. Oligonucleotides site-specifically modified by a single platinum complex adduct will be used as substrates to study recognition and binding sites. The zinc finger proteins to be studied initially will be the transcription factor Sp1 (Cys2His2 cores) and the repair protein XPA. (Cys4 core). The rates of ligand exchange, the possible incorporation of platinum into the peptide, zinc ejection, and loss of conformation will be evaluated. The fundamental chemistry underlying this metal exchange will be studied by the preparation and structural characterization of model platinum and zinc containing complexes. The possibilities for selective recognition between essential aromatic amino acids and platinated nucleobase compounds through the enhanced pi stacking between platinated nucleobases and tryptophan will be investigated by spectroscopic and computational methods. This project will lead to a deeper understanding of the role of DNA conformation in protein recognition, how the nature of DNA damage affects downstream protein processing and DNA repair and perhaps eventually isolation of DNA-protein adducts in vivo. The broader impacts will be to include undergraduate as well as graduate researchers in the activities. International collaborations with the Czech Republic and Israel will be fostered. The long-term impact of this work for society will be to expand the knowledge base; to challenge in a rational and innovative manner the status of current concepts and to lay the groundwork for development of new medicines.