Abstract Hepatitis B virus (HBV) chronic infection represents a major worldwide public health threat leading to cirrhosis and hepatocellular carcinoma. Current treatments for chronic HBV infection include interferon-α and nucleos(t)ides such as lamivudine, telbivudine, adefovir, entecavir, and tenofovir. Unfortunately, none of these therapies offer a satisfactory clinical cure rate. Hence, there remains an unmet medical need for novel and more effective drugs for treatment of HBV infection. Recently, several classes of naturally occurring and synthetic nonnucleoside small molecule HBV inhibitors have been discovered. This review captures important progress on this front in terms of the structural class, mechanism of action, and biological activities. It is conceivable that some of these discoveries might eventually lead to better cure rate of the chronic HBV infection.
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