Human ribonucleotide reductase (RR) is the rate-limiting enzyme for DNA synthesis in cells by conversion of ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs). RRM2 and RRM2B are the regulatory subunits containing a diferric-tyrosyl radical cofactor that is essential for enzyme activity. Osalmid, an approved choleretic drug, is a potential RRM2-targeting inhibitor with an IC50 value of 8.23 μM. In HepG2.2.15 cells, osalmid suppressed the cellular RR activity in a time- and dose-dependent manner. The IC50 in HepG2.2.15 cell lysates was 760.8 μM for osalmid. In HBV DNA-integrated HepG2.2.15 liver cancer cells, osalmid significantly inhibited HBV DNA replication in a time- and dose-dependent manne. Furthermore, osalmid promoted a dose-dependent inhibition of HBV cccDNA levels, suggesting that it can inhibit the synthesis of both HBV genomic DNA and viral cccDNA in infected liver cells. The EC50 for HBV DNA inhibition were 11.1 μM for culture supernatant and 16.5 μM for cells. In HBV-transgenic mice, oral dosing of osalmid at 400 mg/kg/d resulted in a time-dependent inhibition of HBV DNA replication. After treatment for 4 weeks, osalmid suppressed HBV DNA replication by about 40-45% as compared to the control in mouse sera and liver tissues[3].
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