Novel Inorganic Nucleases

描述（由申请人提供）：传统药物开发主要集中在蛋白质靶点上。这反映了细胞蛋白质的不同结构和催化作用，为代谢和感染性疾病提供了合适的靶点。蛋白质结构的复杂性也为有机分子的高度选择性识别提供了机会，利用空间和键合限制将药物映射到蛋白质靶点。这种方法已成功地用于治疗源自酶功能的结构或催化扰动的疾病状态。无机化学在药物开发中的作用受到严重限制，金属离子仅在外围被招募到药物设计中，或者作为有机配体通过与金属蛋白的金属辅因子配位结合的靶点，或者很少作为活性络合物。DNA也是药物开发的研究重点，在这种情况下，顺铂是无机复合物在疾病治疗中最突出的应用之一。然而，DNA在识别特定序列方面存在重大问题。通常，这需要使用具有连接的金属络合物的互补寡核苷酸，并且这种方法严重限制了可以有效开发的范围。第三个靶点是RNA，虽然RNA的许多结构和化学特征使其成为有吸引力的药物靶点，但它以前没有得到其他两个靶点的识别强度。最重要的是，RNA没有细胞修复机制。由于RNA病毒引起的许多疾病状态，在开发有效的化疗治疗时应考虑能够特异性或选择性结合RNA的化合物。 氨基糖苷铜被证明是DNA和RNA靶的高效切割催化剂。这种催化剂介导氧化和水解途径，并且它们的裂解反应显示酶样Michaelis-Menten动力学行为。RNA靶点的体外和体内切割均已得到证实，该提议旨在扩大我们对RNA靶点选择性结合和切割的化学机制的理解，并改善其作为真正无机药物的用途。

DESCRIPTION (provided by applicant): Traditional drug development has focused primarily on protein targets. This reflects the diverse structural and catalytic roles of cellular proteins that provide for opportune targets in metabolic and infectious disease. The complexity of protein structure also affords an opportunity for highly selective recognition by organic molecules, using spatial and bonding constraints to map drugs to protein targets. Such approaches have been successfully used in the treatment of disease states that derive from structural or catalytic perturbations of enzyme function. The role of inorganic chemistry in drug development has been severely limited and metal ions have been recruited into drug design only peripherally, either as a target for binding of an organic ligand through coordination to the metal cofactor of a metalloprotein, or, rarely, as an active complex. DNA has also served as a focus of investigation for drug development, and in this case cisplatin is an example of one of the most prominent applications of inorganic complexes in the treatment of disease. However, DNA poses significant problems with regard to recognition of specific sequences. Typically this requires the use of complementary oligonucleotides with an attached metal complex and such an approach severely limits the scope of what can be usefully developed. A third target, RNA, has not previously received the intensity of recognition afforded to the other two, although many structural and chemical features of RNA make it attractive as a drug target. Most important, there is no cellular repair mechanism for RNA As a result of the many disease states caused by RNA viruses, compounds that are capable of specific or selective binding to RNA should be considered in developing effective chemotherapeutic treatments. Copper aminoglycosides are demonstrated to be highly efficient cleavage catalysts for DNA and RNA targets. Such catalysts mediate both oxidative and hydrolytic pathways and their cleavage reactions display enzymelike Michaelis-Menten kinetic behavior. Both in vitro and in vivo cleavage of RNA targets have been demonstrated, and this proposal seeks to expand our understanding of the chemical mechanisms underlying the selective binding and cleavage of RNA targets and improve develop their use as bona fide inorganic drugs.