Novel Inorganic Nucleases

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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.