Affiliation: Triangle Pharmaceuticals, Inc., 4611 University Dr., Durham, NC 27707 USA
Human immunodeficiency virus (HIV) and Hepatitis B virus (HBV) present extreme health threats worldwide. Although there are approved drugs for both infections, they have significant limitations including toxicities associated with chronic administration, complex dosing regimens, pharmacokinetic interactions and the development of resistance. These limitations are driving the continued search for new agents with improved clinical profiles. A key target for therapeutic intervention for both viruses are the virally encoded polymerases. The HIV RNA directed DNA polymerase (reverse transcriptase, RT) has been extensively studied. The HBV polymerase has not been successfully cloned expressed and purified. Consequently detailed enzymatic / structural analysis has not been carried out. However, high primary sequence homology and functional similarity between HIV RT and HBV polymerase suggest that HIV RT can serve as a model for the study of the HBV encoded enzyme. HIV RT catalyzes the synthesis of double str anded viral DNA using genomic RNA as a template by a bireactant-biproduct mechanism. In this mechanism, the RT, the primed genomic RNA (template) and a natural 2-deoxynucleotide (dNTP) substrate form a ternary complex. The molecular forces that direct the affinity and specificity of the binding, and the reactivity of the nucleic acid templates and dNTP substrates were studied extensively using biophysical, kinetic, and solid state X-ray techniques. The results of these studies are reviewed here and discussed in the context of the opportunity they offer for establishing structure-activity relationships to direct the design of a new generation of antiviral agents with better clinical and resistance profiles.