RNA as a drug target: NMR structures of viral RNA complexes with linear and cyclic peptides

There is a dire need for the development of new strategies to combat infectious disease. The lack of effective vaccines for many pathogens necessitates the development of chemotherapeutic strategies to fight infection by theses pathogens. Effective therapeutic intervention requires robust targets. Most effective antibiotics and antiviral agents bind to a key component of an important biochemical processes in the pathogen such as protein synthesis, DNA synthesis, and cell wall synthesis.; RNA plays a central role in many essential biochemical processes that are often particular to a pathogen including protein synthesis and gene expression. Antibiotics that target RNA are widely used in clinical medicine, and provide an important precedent in demonstrating the possibility of inhibiting RNA-mediated processes that are specific to a particular pathogen or class of pathogens. While there are currently no anti-viral agents that target RNA-mediated events, the potential for selective anti-viral therapy is there. RNA-mediated processes are just as important for the proliferation of viruses as any other organism. Retroviruses such as HIV are particularly suited to RNA-targeted chemotherapy.; To understand the potential of RNA as a drug target from a structural perspective, I have studied the structure of viral RNA from bovine immunodeficiency virus in complex with a linear and cyclic peptide by nuclear magnetic resonance spectroscopy. The high-resolution structure of a linear peptide in complex with RNA has revealed features of RNA recognition that may lead to the development of RNA-targeted drugs. Using the lessons learned from the high-resolution structure, a cyclic peptide was designed and shown to form a 1:1 complex with the RNA with a structure similar to that of the linear peptide-RNA complex.