title: Assembly-directed antivirals differentially bind quasiequivalent pockets to modify hepatitis B virus capsid tertiary and quaternary structure.
abstract: Hepatitis B virus (HBV) is a major cause of liver disease. Assembly of the HBV capsid is a critical step in virus production and an attractive target for new antiviral therapies. We determined the structure of HBV capsid in complex with AT-130, a member of the phenylpropenamide family of assembly effectors. AT-130 causes tertiary and quaternary structural changes but does not disrupt capsid structure. AT-130 binds a hydrophobic pocket that also accommodates the previously characterized heteroaryldihydropyrimidine compounds but favors a unique quasiequivalent location on the capsid surface. Thus, this pocket is a promiscuous drug-binding site and a likely target for different assembly effectors with a broad range of mechanisms of activity. That AT-130 successfully decreases virus production by increasing capsid assembly rate without disrupting capsid structure delineates a paradigm in antiviral design, that disrupting reaction timing is a viable strategy for assembly effectors of HBV and other viruses.
authors.affiliation: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Sarah P
authors.initials: SP
authors.lastname: Katen
authors.forename: Zhenning
authors.initials: Z
authors.lastname: Tan
authors.forename: Srinivas Reddy
authors.initials: SR
authors.lastname: Chirapu
authors.forename: M G
authors.initials: MG
authors.lastname: Finn
authors.forename: Adam
authors.initials: A
authors.lastname: Zlotnick
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D001549:Benzamides / Q000737:chemistry*; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry / Q000648:ultrastructure; D036022:Capsid Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006515:Hepatitis B virus / Q000502:physiology / Q000648:ultrastructure*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D019065:Virus Assembly / Q000187:drug effects*
chemical_list: C471028:AT 130; D000998:Antiviral Agents; D001549:Benzamides; D036022:Capsid Proteins; D021122:Protein Subunits; D011743:Pyrimidines