MOLECULAR AND STRUCTURAL APPROACHES TO ANTIVIRALS

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The use of traditional target-based design strategies to identify clinically useful antiviral agents has been hampered by the tendency of most candidate antiviral agents to be highly toxic. The toxicity arises due to an apparent tendency of viruses to "borrow" functions from the host, resulting in significant homologies between potential viral targets and cellular homologues. Recent developments in the field of computational methods for structure-based drug design, provide the opportunity to design macromolecular ligand based on the structure of the target molecule alone without necessary reference to known substrates or inhibitors. These methods, which are still in the development stage, may permit the design of antiviral agents with significantly lower cross- reactivity with essential host functions. This application proposes to continue a program of joint development and applications of structure- based methods to design antiviral agents targeting several well- characterized target proteins of poliovirus, including the capsid itself, the viral RNA-dependent RNA polymerase (3D), and a protease-polymerase precursor (3CD) which plays multiple roles in the viral life cycle; and to extend design studies to a new target, the oligomerization domain of the capsid protein of hepatitis delta virus (HDV). Preliminary studies have resulted in the determination of the structures of six poliovirus/capsid- binding drug complexes, the design of a new class of capsid binding drug using the program MCSS (developed by Miranker and Karplus), and the crystallization of oligomerization domain of the HDV capsid protein. These studies will be extended to initiate a second round of design of capsid binding drugs, to extend the use of MCSS to design inhibitors of 3D, to crystallize and solve the structure of 3CD and use the new structure to design agents which inhibit its proteolytic and RNA binding activities, and to solve the structure of the HDV peptide and use this structure to design agents which block the assembly of the capsid protein and as a basis of vaccine design. In order to facilitate the concurrent development of the application and the computational design methodologies, all design studies will be performed in collaboration with the drug-design group in Martin Karplus's laboratory.