title: Optimization and Synthesis of Pyridazinone Derivatives as Novel Inhibitors of Hepatitis B Virus by Inducing Genome-free Capsid Formation.
abstract: The capsid of hepatitis B virus (HBV) plays a vital role in virus DNA replication. Targeting nucleocapsid function has been demonstrated as an effective approach for anti-HBV drug development. A high-throughput screening and mechanism study revealed the hit compound 4a as an HBV assembly effector (AEf), which could inhibit HBV replication by inducing the formation of HBV DNA-free capsids. The subsequent SAR study and drug-like optimization resulted in the discovery of the lead candidate 4r, with potent antiviral activity (IC50= 0.087 ± 0.002 μM), low cytotoxicity (CC50= 90.6 ± 2.06 μM), sensitivity to nucleoside analogue-resistant HBV mutants, and synergistic effect with nucleoside analogues in HepG2.2.15 cells.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Lu
authors.affiliation: Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Xing
authors.affiliation: Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Xiankun
authors.initials: X
authors.lastname: Tong
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Chunlan
authors.initials: C
authors.lastname: Feng
authors.affiliation: Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zuo
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 ZuChongZhi Road, Shanghai 201203, China.
authors.forename: Youhong
authors.identifier: 0000-0003-1770-6272
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000378:metabolism*; D024882:Drug Resistance, Viral / Q000187:drug effects; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D013329:Structure-Activity Relationship; D019065:Virus Assembly / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001549:Benzamides
keywords: HBV DNA-free capsids; SAR study; drug-like optimization; lead candidate; pyridazinone