1. Volume 132, Issue 4, Pages 1574-1585 (April 2007)
Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B 
Marc Ghany, T. Jake Liang 
Gastroenterology 
Volume 132, Issue 4, Pages (April 2007)
DOI: /j.gastro
Copyright © 2007 AGA Institute Terms and Conditions

2. Figure 1
Organization of HBV genome. The inner circle depicts the HBV genome with the polymerase (dark circle) attached to the 5′ end of the minus strand and a capped oligoribonucleotide (corkscrew) attached to the 5′ end of the incomplete plus strand. Two, 11-base pair direct repeats located at the 5′ end of the minus and plus strands, DR 1 and DR 2, are important for strand-specific synthesis. The 4 open reading frames are shown between the inner and outer circles and consist of the pre-C/core genes, the polymerase gene, the pre-S1, pre-S2 and S genes, and the X gene. The outer circle shows the 4 major viral mRNAs, the 3.5-kilobase (kb) core or pregenomic mRNA, the 2.4-kb pre-S1 mRNA, 2.1-kb pre-S2/S mRNA, and the 0.7 kb X mRNA. All mRNAs share a common poly-A 3′ end.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions

3. Figure 2
Replication cycle of HBV and molecular targets of HBV replication. The virus enters the hepatocyte via an unknown mechanism, and the viral genome is transported to the nucleus in which cccDNA is generated by repairing the partially double-stranded genome, whereupon viral transcription occurs. Encapsidation of the pregenomic RNA occurs in the cytoplasm via a complex interaction among epsilon, core particles, HBV polymerase, and various chaperone proteins. Reverse transcription leading to negative- and then positive-strand synthesis occurs within the viral nucleocapsid. Viral assembly takes place in the endoplasmic reticulum (ER). “Mature” nucleocapsids undergo assembly and coating with envelope proteins followed by budding and virion secretion into the blood. Nucleoside analogues inhibit the production of HBV DNA by competitively inhibiting the HBV polymerase and/or acting as chain terminators (not all NAs are chain terminators). Phenylpropenamide inhibits the encapsidation process, and HAP acts by inhibiting the encapsidation step and degradation of the nucleocapsid. Peptidomimetic compounds act further downstream by inhibiting assembly of the HBV. Glucosidase inhibitors act by inhibiting the glycosylation of hepatitis B surface proteins and thereby inhibit assembly of the virus.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions

4. Figure 3
(A) Schematic of the HBV polymerase open reading frame illustrating the 4 functional domains and the 7 catalytic subdomains A–G. (B) Proposed structure of the HBV polymerase based on the model of HIV-1 RT and adapted from Das et al33 and Bartholomeusz et al.52 As illustrated in this ribbon diagram, the HBV polymerase has a right-handed configuration with thumb, palm, and fingers domains. The approximate positions of the conserved domains A–E are shown by the colored ribbons Domains A, C, and perhaps D participate directly in dNTP binding and catalysis. Domains B and E are involved with precise positioning of the primer-template relative to the active site. (C) Location of the major lamivudine mutations relative to the conserved domains. (D) Location of the major adefovir and tenofovir mutations relative to the conserved domains. (E) Location of the major entecavir mutations relative to the conserved domains.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions

5. Figure 4
Chemical structures of the 3 main classes of nucleos(t)ide analogues with anti-HBV activity. (A) Lamivudine, emtricitabine, telbivudine, and clevudine are nucleoside analogs with the unnatural β L-configuration. Lamivudine and its 5′ fluoro derivative emtricitabine lack the 3′-OH of the deoxyribose, which is replaced with a sulfur molecule and act as chain terminators. Telbivudine and clevudine possess the 3’-OH group of the β-L-2’-deoxyribose that confers specific anti-HBV activity. Following intracellular phosphorylation to the triphosphate, and, after removal of the diphosphate group, the monophosphate is incorporated at the 3′ end of the viral DNA chain. (B) Adeofovir dipivoxil and tenofovir disoproxil fumarate are acyclic nucleotide analogues. They possess a phosphonate group that is equivalent to a phosphate group but cannot be cleaved by the esterases. Adefovir and tenofovir differ by a single methyl group, which differentiates the molecules with respect to safety. As with lamivudine and emtricitabine, they lack the 3′-OH group and function as chain terminators. Following intracellular phosphorylation to the diphosphate form, and, after removal of the diphosphate group, they are incorporated at the 3′ end of the viral DNA chain. (C) Entecavir and Abacavir are carbocyclic analogues of 2′-deoxyguanosine. The oxygen in the furanose ring is replaced by a vinyl group with Entecavir. Entecavir has specific anti-HBV activity with little activity against HIV or other DNA viruses, whereas Abacovir is active against HIV-1 and -2. Entecavir inhibits HBV polymerase via several mechanisms including priming, reverse transcription, and DNA elongation.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions