Inhibition of Hepatitis B Virus Polymerase Using Entecavir

Entecavir (Baraclude) is a deoxyguanosine nucleoside analog approved for the treatment of hepatitis B virus (HBV) infection.

According to a report in the January 31, 2007 electronic edition of the Journal of Virology, entecavir differs from other the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) approved for HBV therapy -- lamivudine (Epivir-HBV) and adefovir (Hepsera) -- in several ways:

• Entecavir is more than 100-fold more potent against HBV in culture.

• Entecavir displays no significant activity against HIV.

• While lamivudine and adefovir are obligate DNA chain terminators, entecavir halts HBV DNA elongation after incorporating a few additional bases.

Researchers from Bristol-Myers Squibb (the maker of entecavir) used 3-dimensional homology models of the catalytic center of the HBV RT/DNA/dNTP complex, based on the HIV RT/DNA structure, with in vitro enzyme kinetic studies, to examine the mechanism of action of entecavir against HBV reverse transcriptase (RT).

Results

• A novel hydrophobic pocket in the rear of the RT dNTP binding site that accommodates the exocyclic alkene moiety of entecavir was predicted, establishing a basis for the observed superior potency.

• HBV DNA chain termination by entecavir was accomplished through disfavored energy requirements as well as steric constraints during subsequent nucleotide addition.

• Validation of the model was accomplished through modeling of lamivudine resistance substitutions, which cause an 8-fold decrease in entecavir susceptibility and are predicted to reduce -- but not eliminate -- the entecavir-binding pocket, in agreement with experimental observations.

• Adefovir resistance changes did not affect the entecavir docking model, also agreeing with experimental results.

Conclusion

Overall, the investigators concluded, "these studies explain the potency, mechanism, and cross-resistance profile of entecavir against HBV and account for the successful treatment of naive and lamivudine- or adefovir-experienced chronic HBV patients."

02/20/07

Reference
D R Langley, A W Walsh, C J Baldick, and others. Inhibition of Hepatitis B Virus Polymerase by Entecavir. Journal of Virology. January 31, 2007 [Epub ahead of print].