Danoprevir Sodium

Hepatitis B virus (HBV) is a 3.2 kb hepatotropic DNA that possesses a unique episomal DNA form known as covalently closed circular DNA (cccDNA). cccDNA is the major risk factor for persistent HBV infection and consequently causes chronic liver diseases such as hepatitis, cirrhosis, and hepatocellular carcinoma. To prevent the progression of liver disease, eradication of HBV, especially cccDNA, is essential. In this study, we established a drug screening system using artificial recombinant HBV cccDNA (rcccDNA), which is regulated by a loxP-HBV genome and CRE expression. To identify potential drugs targeting cccDNA, a total of 379 antiviral reagents were tested. Among them, several chemicals including danoprevir, L- and D-cycloserine, phenytoin sodium, amantadine, and germacrone showed a decrease in cccDNA levels. Especially, D-cycloserine diminished the secretion of HBV antigens and induced cccDNA degradation in the HBV infection system. This screening system helps to develop the therapeutic drug target to cccDNA This screening system may help develop therapeutic drugs targeting cccDNA.

The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by cytochrome P450 3A7 (CYP3A7) in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the 13 HCV antivirals we investigated, 8 (∼62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 µM. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 µM, which is physiologically relevant in comparison with the K_m of dehydroepiandrosterone-sulfate (DHEA-S) oxidation (reported to be between 5 and 20 µM). We also discovered that paritaprevir is a time-dependent inhibitor of CYP3A7, which shifts the IC₅₀ ∼twofold from 11 µM to 5 µM. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K_I and K_inact values of 4.66 µM and 0.00954 minute^-1, respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones. SIGNIFICANCE STATEMENT: The prevalence of HCV in pregnant people is estimated at between 1% and 8% of the global population, yet little to no information exists about the risk antiviral treatment poses to the developing fetus. There is a potential risk of drugs adversely affecting mother-fetal communication by inhibiting fetal hepatic CYP3A7, an integral enzyme for estriol production. We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development.