The P.I. notes that despite the availability of safe and effective vaccines, hepatitis B virus (HBV) infection remains a serious global health issue today and that therefore, this renewal application deals with a continuation of interdisciplinary collaborative efforts at the University of Georgia and Yale University for drug design, synthesis and biological evaluation of nucleoside analogues as potential anti-HBV agents. The P.I. states that this project is based on their recent findings that L-nucleosides are a new promising class of anti-HBV agents. He reports that during their drug discovery efforts supported by the current grant beta-L-2'-fluoro-5-methyl-arabinofuranosyluracil (L-FMAU) was discovered as a potent and non-toxic anti-HBV agent in in vitro 2.2.15 cells as well as in vivo in the duck hepatitis virus model and that L-FMAU is currently being considered as a clinical candidate by a pharmaceutical firm. He notes that in view of these highly encouraging preliminary results, in this application, it is proposed to continue on the chemical synthesis and biological evaluation of the nucleosides with unnatural configuration (L-nucleosides) as potential anti-HBV agents. It is stated that the proposed specific aims are: a) synthesis of 2'-fluorinated L-purine nucleosides (Class I), b) synthesis of 3'- heteroatom-substituted 2',3'-dideoxynucleoside analogues (Class II), c) synthesis of 2',3'-unsaturated- and 2',3'-dideoxy-L- nucleosides (Class III), d) synthesis of L-carbocyclic nucleosides (Class IV), e) 3'-hydroxymethyl-substituted L-nucleosides (Class V), f) synthesis of acyclonucleosides, g) evaluation of anti-HBV efficacy in in vitro a 2.2.15 cell system as well as combination studies with other anti-HBV agents, h) in vitro cytotoxicity studies to determine the preliminary toxicity, i) studies of mode of action of promising anti-HBV agents, and j) in order to assess the discovered promising anti-HBV nucleosides as potential clinical candidates, in vivo studies in the Pekin duck and woodchuck hepatitis models are to be conducted in collaboration with investigators in France and at the NIH. The long term goal of this application is to discover safe and effective anti-HBV drugs, which can be used as a single agent or in combination with other clinically effective and safe anti-HBV agents with different modes of action as well as toxicity.
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