Antiviral Drug Discovery for Drug Resistant Hepatitis B Virus
소속 :
연사 : C.K. (David) Chu(The University of Georgia College of Pharmacy)
일시 : 2012-05-02 17:00 ~
장소 : 500동 목암홀
일 시 : 2012년 5월 2일, 5:00 PM
장 소 : 500동 목암홀
-Abstract-
Long-term anti-HBV nucleosi(t)de therapy is often associated with drug resistance which significantly compromises the clinical application of these agents. Therefore, novel antiviral agents active against drug-resistant HBV are critically needed. In order to search for nucleosides active against drug-resistant HBV, modifications with fluorine substitution on the 2"-position of carbocyclic nucleosides were carried out. FMCA and its phosphoramidate were synthesized according to the newly developed synthetic procedures. The synthesized compounds were evaluated against wild type HBV as well as lamivudine-, adefovir- and entecavir-resistant HBV mutants. FMCA and its prodrug maintained antiviral potency against adeforvir- and lamivudine-resistant HBV mutants (N236T and M204V, M204I, L180M, M204I/V, respectively) in vitro. Furthermore, FMCA & its prodrug were also active against the entecavir/lamivudine triple mutant (L180M/M204V/S202G). The potency of the monophosphate prodrug was 10 fold greater than that of the nucleoside against wild-type (WT) as well as drug-resistant mutants. In order to determine the anti-HBV activity in vivo, FMCA phosphoramidate was evaluated in chimeric mice infected with WT and the entecavir/lamivudine triple mutant. The prodrug reduced the serum HBV DNA level by 2.2 log copies in mice infected with the WT clone, while in mice infected with entecavir/lamivudine-resistant clone, reduction of 1.2 log copies was observed.
In view of the observed significant anti-HBV activity in vitro and in vivo against wild-type as well as the drug-resistant mutants without significantly increase of mitochondrial toxicity, their preclinical studies are warranted (Supported by NIH grant AI-25899).
장 소 : 500동 목암홀
-Abstract-
Long-term anti-HBV nucleosi(t)de therapy is often associated with drug resistance which significantly compromises the clinical application of these agents. Therefore, novel antiviral agents active against drug-resistant HBV are critically needed. In order to search for nucleosides active against drug-resistant HBV, modifications with fluorine substitution on the 2"-position of carbocyclic nucleosides were carried out. FMCA and its phosphoramidate were synthesized according to the newly developed synthetic procedures. The synthesized compounds were evaluated against wild type HBV as well as lamivudine-, adefovir- and entecavir-resistant HBV mutants. FMCA and its prodrug maintained antiviral potency against adeforvir- and lamivudine-resistant HBV mutants (N236T and M204V, M204I, L180M, M204I/V, respectively) in vitro. Furthermore, FMCA & its prodrug were also active against the entecavir/lamivudine triple mutant (L180M/M204V/S202G). The potency of the monophosphate prodrug was 10 fold greater than that of the nucleoside against wild-type (WT) as well as drug-resistant mutants. In order to determine the anti-HBV activity in vivo, FMCA phosphoramidate was evaluated in chimeric mice infected with WT and the entecavir/lamivudine triple mutant. The prodrug reduced the serum HBV DNA level by 2.2 log copies in mice infected with the WT clone, while in mice infected with entecavir/lamivudine-resistant clone, reduction of 1.2 log copies was observed.
In view of the observed significant anti-HBV activity in vitro and in vivo against wild-type as well as the drug-resistant mutants without significantly increase of mitochondrial toxicity, their preclinical studies are warranted (Supported by NIH grant AI-25899).
