Entecavir Patent Evaluation & Genotoxicity

Abstract

Entecavir is an oral antiviral drug used in the treatment of hepatitis B infection. Entecavir is a guanosine nucleoside analogue with selective activity against Hepatitis B Virus (HBV), which inhibits reverse transcription, The initial patent on entecavir expired in South Africa in 2011 ZA 1991/07894. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs against hepatitis B virus [1]. It has reported that entecavir gave positive responses in both genotoxicity and carcinogenicity assays. However the genotoxic mechanism of entecavir remains elusive. To evaluate the genotoxic mechanisms, we analyzed the effect of entecavir on a panel of chicken DT40 B-lymphocyte isogenic mutant cell line deficient in DNA repair and damage tolerance pathways. Our results showed that Parp1-/mutant cells defective in Single-Strand Break (SSB) repair were the most sensitive to entecavir. Brca1-/-, Ubc13-/and translesion-DNA-synthesis deficient cells including Rad18-/and Rev3-/were hypersensitive to entecavir. XPA-/mutant deficient in nucleotide excision repair was also slightly sensitive to entecavir. γ-H2AX foci forming assay confirmed the existence of DNA damage by entecavir in Parp1-/-, Rad18-/and Brca1-/mutants. Karyotype assay further showed entecavir-induced chromosomal aberrations, especially the chromosome gaps in Parp1-/-, Brca1-/-, Rad18-/and Rev3-/cells when compared with wild-type cells. These genetic comprehensive studies clearly identified the genotoxic potentials of entecavir and suggested that SSB and postreplication repair pathways may suppress entecavir-induced genotoxicity.