Identification of a novel long-acting 4’-modified nucleoside reverse transcriptase inhibitor against HBV


Higashi-Kuwata N, Hayashi S, Kumamoto H, Ogata-Aoki H, Das D, Venzon D, Hattori SI, Bulut H, Hashimoto M, Otagiri M, Takamune N, Kishimoto N, Davis D, Misumi S, Kakuni M, Tanaka Y, Mitsuya H. Identification of a novel long-acting 4'-modified nucleoside reverse transcriptase inhibitor against HBV. J Hepatol. 2020 Dec 14:S0168-8278(20)33843-5. doi: 10.1016/j.jhep.2020.12.006. Epub ahead of print. PMID: 33333207.

Background & Aims:
While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects are yet to be optimized and the emergence  of NRTI-resist ant HBV variants is an issue because of the  requirement for lifelong treatment. The development of agents that more profoundly suppress wild-type and drug-resistant HBVs, and that have a long-acting effect, are crucial to improve patient outcomes.

Authors synthesized a novel long-acting 4’-modified NRTI termed E-CFCP.  In this study, they tested its anti-HBV activity in vitro, before evaluating its anti-HBV activity in HBV-infected human-liver-chimeric mice (PXB-mice). E-CFCP’s long-acting features and E-CFCP-triphosphate’s interactions with the HBV reverse transcriptase (HBV-RT) were examined.

E-CFCP represents the first reported potential long-acting NRTI with potent activity against wild-type and treatment-resistant HBV.