Assembly-Directed Antivirals Differentially Bind Quasiequivalent Pockets to Modify Hepatitis B Virus Capsid Tertiary and Quaternary Structure

• Published in: Structure (London) Vol. 21; no. 8; pp. 1406 - 1416
• Main Authors: Katen, Sarah P., Tan, Zhenning, Chirapu, Srinivas Reddy, Finn, M.G., Zlotnick, Adam
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.08.2013
• Subjects: Antiviral Agents - chemistry; Assembly; Benzamides - chemistry; Binding Sites; Capsid - chemistry; Capsid - ultrastructure; Capsid Proteins - chemistry; Crystallography, X-Ray; Disrupting; Effectors; Hepatitis B virus; Hepatitis B virus - physiology; Hepatitis B virus - ultrastructure; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Pocket; Protein Binding; Protein Structure, Quaternary; Protein Structure, Secondary; Protein Structure, Tertiary; Protein Subunits - chemistry; Pyrimidines - chemistry; Strategy; Surface chemistry; Virus Assembly - drug effects; Viruses
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2013.06.013

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. [Display omitted] •Phenylpropenamides induce tertiary and quaternary structural changes in HBV capsids•AT-130 binds to a promiscuous pocket at the dimer-dimer interface•AT-130 favors a unique quasiequivalent binding site in the capsid•Small molecules that do not disrupt capsid structure are still effective antivirals AT-130 is an antiviral compound that stimulates inappropriate hepatitis B virus (HBV) assembly. Katen et al. determine a structure for the T = 4 icosahedral HBV capsid in complex with AT-130 and show that the binding to a quasiequivalent binding site leads to distinct tertiary and quaternary structural changes.