title: 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: in vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action.
abstract: Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (FMCA) monophosphate prodrug (FMCAP) was synthesized and evaluated for its in vitro anti-HBV potency against a lamivudine-entecavir resistant clone (L180M+M204V+S202G). FMCA demonstrated significant antiviral activity against wild-type as well as lamivudine-entecavir resistant triple mutant (L180M+M204V+S202G). The monophosphate prodrug (FMCAP) demonstrated greater than 12-fold (12×) increase in anti-HBV activity without increased cellular toxicity. Mitochondrial and cellular toxicity studies of FMCA indicated that there is no significant toxicity up to 100 μM. Mode of action studies by molecular modeling indicate that the 2'-fluoro moiety by hydrogen bond as well as the Van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug-resistant mutants.
authors.affiliation: The University of Georgia, College of Pharmacy, Athens, GA 30602, USA.
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Rawal
authors.forename: Uma S
authors.initials: US
authors.lastname: Singh
authors.forename: Satish N
authors.initials: SN
authors.lastname: Chavre
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.forename: Masaya
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Wai
authors.initials: W
authors.lastname: Hung
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Govindarajan
authors.forename: Brent
authors.initials: B
authors.lastname: Korba
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D019259:Lamivudine / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: C581770:2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate; C569519:2'-fluoro-6'-methylene-carbocyclic adenosine; D000998:Antiviral Agents; D011355:Prodrugs; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D000241:Adenosine