Abstract
Hepatitis B virus (HBV) infection is a prime cause of liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma. The current drugs clinically available are nucleot(s)ide analogues that inhibit viral reverse transcriptase activity. Most drugs of this class are reported to have viral resistance with breakthrough. Recent advances in methods for in silico virtual screening of chemical libraries, together with a better understanding of the resistance mechanisms of existing drugs have expedited the discovery and development of novel anti-viral drugs. This review summarizes the current status of knowledge about and viral resistance of HBV drugs, approaches for the development of novel drugs as well as new viral and host targets for future drugs.
Highlights
Hepatitis B virus (HBV), the prototype of the Hepadnaviridae family, is a small virus harboring only four open reading frames
Chronic HBV infection is strongly associated with liver diseases like chronic hepatic insufficiency, cirrhosis, and hepatocellular carcinoma (HCC) [1,2,3,4]
The World Health Organization (WHO) estimates that there are currently 400 million individuals worldwide who are chronically infected with HBV, of whom 100 million eventually will die of chronic liver diseases or HCC [5,6]
Summary
Hepatitis B virus (HBV), the prototype of the Hepadnaviridae family, is a small virus harboring only four open reading frames. HBV expresses four major viral antigens: precore/core, surface, polymerase and HBV X protein (HBx). Among these HBV-encoded proteins, viral polymerase is the key protein for genome replication and consists of terminal protein (following a spacer), reverse transcriptase (RT), and RNAse H domains. The RT domain is responsible for the minus strand DNA synthesis, the first step in HBV replication, from the pregenomic RNA template [7,8]. All drugs approved as anti-HBV agents are reported to have viral resistance due to specific mutations in the RT domain, which encourage the development of novel anti-HBV agents targeting non-polymerase viral or host proteins. In this review we summarize the current status of antiHBV agents with their viral resistance and the novel small chemical anti-HBV agents targeting nonpolymerase proteins
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