Zinc Fingers as Templates for Metal and Metal-DNA Interactions

生命过程化学（CLP）计划的这项研究奖支持弗吉尼亚联邦大学的Nicholas Farrell教授的工作，以探索铂金属络合物与锌指蛋白和模型锌螯合物的基础化学和生物学。 拟议的工作集中在一系列与所谓的锌指，锌离子的小蛋白质组装体和半胱氨酸或组氨酸残基的组合的配位化学有关的研究上，这些残基在蛋白质和其他生物分子（如RNA和DNA）的结构稳定性中起着关键作用。 锌指化学的新模式，探索通过认识烷基化和金属间化合物之间的概念类比。 这些模式包括分子识别和亲电攻击的铂金属化合物上的锌硫醇键。 锌指蛋白参与许多生物学过程，如转录和DNA修复，并且它们是病毒性疾病和癌症的治疗干预的重要靶点。对锌的“配位化学”的研究在迄今未被认识的方向上扩展了这类重要蛋白质的已知性质。 这项研究将为具有生物活性的无机化合物提出新的作用机制和新的靶点，并为新的医学应用提供长期的可能性。 该项目的更广泛影响还包括培训本科生和研究生，包括与巴西、中国和捷克共和国的机构开展联合活动。

This research award in the Chemistry of Life Processes (CLP) program supports work by Professor Nicholas Farrell at Virginia Commonwealth University to explore the fundamental chemistry and biology of platinum-metal complexes with zinc finger proteins and model zinc chelates. The proposed work centers on a series of studies pertaining to the coordination chemistry of the so-called zinc fingers, small protein assemblies of zinc ions and a combination of cysteine or histidine residues that play a key role in the structural stability of proteins and other biomolecules such as RNA and DNA. New patterns of zinc-finger chemistry are explored by recognizing the conceptual analogy between alkylation and metallation. These patterns include molecular recognition and electrophilic attack by platinum-metal compounds on zinc-thiolate bonds. Zinc finger proteins are involved in a host of biological processes such as transcription and DNA repair and they are important targets for therapeutic intervention in viral diseases and cancer. The study on the "coordination chemistry" of zinc expands the known properties of this important class of proteins in hitherto unrecognized directions. The research will suggest new mechanisms of action and new targets for biologically active inorganic compounds with long-term possibilities for new medicinal applications. Broader impacts of the project also include the training of undergraduate and graduate students, including joint activities with institutions in Brazil, China, and the Czech Republic.