title: Past, Current, and Future Developments of Therapeutic Agents for Treatment of Chronic Hepatitis B Virus Infection.
abstract: For decades, treatment of hepatitis B virus (HBV) infection has been relying on interferon (IFN)-based therapies and nucleoside/nucleotide analogues (NAs) that selectively target the viral polymerase reverse transcriptase (RT) domain and thereby disrupt HBV viral DNA synthesis. We have summarized here the key steps in the HBV viral life cycle, which could potentially be targeted by novel anti-HBV therapeutics. A wide range of next-generation direct antiviral agents (DAAs) with distinct mechanisms of actions are discussed, including entry inhibitors, transcription inhibitors, nucleoside/nucleotide analogues, inhibitors of viral ribonuclease H (RNase H), modulators of viral capsid assembly, inhibitors of HBV surface antigen (HBsAg) secretion, RNA interference (RNAi) gene silencers, antisense oligonucleotides (ASOs), and natural products. Compounds that exert their antiviral activities mainly through host factors and immunomodulation, such as host targeting agents (HTAs), programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors, and Toll-like receptor (TLR) agonists, are also discussed. In this Perspective, we hope to provide an overview, albeit by no means being comprehensive, for the recent development of novel therapeutic agents for the treatment of chronic HBV infection, which not only are able to sustainably suppress viral DNA but also aim to achieve functional cure warranted by HBsAg loss and ultimately lead to virus eradication and cure of hepatitis B.
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Yameng
authors.initials: Y
authors.lastname: Pei
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Chunting
authors.initials: C
authors.lastname: Wang
authors.affiliation: Molecular Design and Chemical Biology, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai , Shanghai 201203, China.
authors.forename: S Frank
authors.initials: SF
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Gang
authors.identifier: 0000-0001-5549-5686
authors.initials: G
authors.lastname: Liu
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D001688:Biological Products / Q000627:therapeutic use; D058492:Drug Repositioning; D050883:HSC70 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000187:drug effects* / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019251:Nucleocapsid / Q000037:antagonists & inhibitors; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D000067492:RNAi Therapeutics; D016914:Ribonuclease H / Q000037:antagonists & inhibitors; D051193:Toll-Like Receptors / Q000819:agonists; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D060890:B7-H1 Antigen; D001688:Biological Products; C423236:CD274 protein, human; D050883:HSC70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C494371:HSPA8 protein, human; D006514:Hepatitis B Surface Antigens; D016376:Oligonucleotides, Antisense; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D051193:Toll-Like Receptors; D016914:Ribonuclease H