Targeting hepatitis B virus cccDNA levels: Recent progress in seeking small molecule drug candidates

Hepatitis B virus (HBV) infection is a major global health problem that puts people at high risk of death from cirrhosis and liver cancer. The presence of covalently closed circular DNA (cccDNA) in infected cells is consid-ered to be the main obstacle to curing chronic hepatitis B. At present, the cccDNA cannot be completely eliminated by standard treatments. There is an urgent need to develop drugs or therapies that can reduce HBV cccDNA levels in infected cells. We summarize the discovery and optimization of small molecules that target cccDNA synthesis and degradation. These compounds are cccDNA synthesis inhibitors, cccDNA reducers, core protein allos-teric modulators, ribonuclease H inhibitors, cccDNA tran-scriptional modulators, HBx inhibitors and other small molecules that reduce cccDNA levels.