The over-all goal of this """"""""fast track"""""""" proposal is to develop a new class of orally available compounds for the treatment of chronic human hepatitis B virus (HBV) infection through a """"""""proof of principle"""""""" Phase I/IIa Human clinical trial. With our colleagues, we have shown that alkylated imino sugars, called """"""""alkovirs,"""""""" are novel and effective in preventing HBV replication in tissue culture systems under conditions where there is no detectable cyto-toxicity. The alkovirs are previously undescribed synthetic (hence completely characterized) small molecules. Unlike the glucosidase inhibitors, (another class of imino sugars that we have been studying) alkovirs do not inhibit glucosidases, making them distinct and conferring certain advantages. Moreover, although alkovirs inhibit HBV replication, they do not target the viral polymerase, as do most nucleoside analogues. Thus, alkovirs should be effective against lamivudine """"""""resistant"""""""" HBV mutants. The objectives of this """"""""fast track"""""""" proposal are intended to be straightforward and defined by clear milestones: In phase I, the Alkovir(s) with the most potent anti-HBV activity against wild type virus and lamivudine resistant virus will be selected and tested for in vivo toxicity and pharmacokinetics in a rat model. In Phase II, the efficacy and toxicity of the candidate Alkovir(s) selected in Phase I will be evaluated in the woodchuck model of chronic hepatitis virus infection both as monotherapy and in combination with 3TC-lamivudine. Other work, to be performed in parallel with this study, will explore the precise mechanism of action of alkovirs and possibility that (a) they are effective against other viruses and (b) are a class of compounds to which mutant viruses do not frequently emerge. Accomplishment of these Aims will permit the introduction of alkovirs for human clinical trials. Given the need to find complements to nucleoside analogues, the introduction of new anti-hepatitis B virus agents as described here is extremely important.
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| Mehta, Anand S; Gu, Baohua; Conyers, Bertha et al. (2004) alpha-Galactosylceramide and novel synthetic glycolipids directly induce the innate host defense pathway and have direct activity against hepatitis B and C viruses. Antimicrob Agents Chemother 48:2085-90 |
| Mehta, Anand; Ouzounov, Serguey; Jordan, Robert et al. (2002) Imino sugars that are less toxic but more potent as antivirals, in vitro, compared with N-n-nonyl DNJ. Antivir Chem Chemother 13:299-304 |
| Mehta, Anand; Conyers, Bertha; Tyrrell, D L J et al. (2002) Structure-activity relationship of a new class of anti-hepatitis B virus agents. Antimicrob Agents Chemother 46:4004-8 |
