Hepatitis B, a liver disease, is the one of most widespread infectious diseases in the world. There are 1.5 million people who become newly infected patients every year. It can spread through blood transfusions and bodily fluids. The symptoms of hepatitis B are yellowish skin, tiredness, abdominal pain, etc., some chronic patients even eventually develop cirrhosis and liver cancer.
Hepatitis B virus (HBV) is the cause of hepatitis B. HBV is a partially double-stranded DNA virus belonging to the genus Orthohepadnavirus. HBV consists of an outer lipid envelope and an icosahedral nucleocapsid core. Specifically, their components are HBsAg (surface antigen), HBeAg (envelope antigen), HBcAg (core antigen), HBx (viral protein), viral DNA, and DNA polymerase which along with pre-genomic RNA. HBV infection changes liver cells in bad ways. For example, it causes ROS increase, changes miRNA expression patterns, influences histone methyltransferases, and thereby induces DNA damage. Nowadays, the inhibition of HBV components has become the treatment strategy.
GST-HG131 is a potent inhibitor of HBV surface antigen.
GST-HG131 belongs to dihydrobenzopyridooxazepine (DBP) series. This inhibitor exhibits excellent and specific HBV antigens inhibition with EC50s of 28.2 nM (HBsAg) and 16.0 nM (HBeAg), respectively. GST-HG131 (500 nM) appears to inhibit HBV antigens through the inhibition of HBV RNAs in a dose- and time-dependent manner. GST-HG131 shows moderate permeability in the Caco-2 assay; also low rat and human plasma protein binding, and low clearance in liver microsomal stability assays.
Besides, in vivo, GST-HG131 (3-30 mg/kg, i.v.; once daily for 4 weeks) also shows HBV inhibition in an AAV/HBV mouse model. Moreover, it exhibits excellent pharmacokinetics properties and tolerance doses. GST-HG131 exhibits low clearance (4.04 mL/min/kg in dog), moderate plasma half-life (3.39 h of T1/2 in dog); high plasma exposure (4850 nM of Cmax and 26500 nM·h of AUC in dog) and oral bioavailability (93% in dog). GST-HG131 (100-1000 mg/kg, p.o., once daily for 14 d) is well tolerated at 300 mg/kg and 100 mg/kg in rat preliminary toxicology study.
In conclusion, GST-HG131 is a potent and specific HBV inhibitor, with excellent pharmacokinetics properties and tolerance doses.