Novel phosphonate nucleoside as antiviral agents

Abstract

The phosphonate nucleosides have been extensively studied as potent antiviral agents since (S)-HPMPA was discovered to exhibit a broad spectrum of antiviral activity against DNA viruses, such as herpes simplex virus (HSV), varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and TK mutants of HSV and VZV. The phosphonate nucleosides inhibit viral replication via a different mode of action from nudeoside agents such as zidovudine (AZT), lamivudine (3TC), didanosine (ddi), aciclovir (ACVj and penciclovir. In contrast to nucleoside agents, the phosphonate nucieosides are intracellularly metabolized to active forms. Their diphosphates, which are incroporated into viral DNA or RNA during DNA or RNA elongation, result in termination of polymerization. Although the phosphonate nucleosides exhibit a broad spectrum of antiviral activity, they have low cellular permeability and low oral bioavailability due to the negative charges of the phosphonate functionality. Therefore, prodrug approaches to masking the negative charges were essential. Three compounds, cidofovir ([S]-HPMPC), tenofovir (PMPA) disoproxil fumarate and adefovir (PMEA) dipivoxil, are currently marketed for the therapy of HCMV infection in HIV patients, HIV and hepatitis 8 virus (HBV), respectively. in addition, MCC-478 (Mitsubishi, Lilly) and LB-80380 (LG Life Sciences) are currently undergoing clinical trials evaluating their anti-HBV efficacy.