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Journal of Virology, October 2008, p. 10262-10270, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01360-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Small-Molecule Effectors of Hepatitis B Virus Capsid Assembly Give Insight into Virus Life Cycle{triangledown}

Christina Bourne,1,{dagger} Sejin Lee,2 Bollu Venkataiah,2 Angela Lee,1 Brent Korba,3 M. G. Finn,2* and Adam Zlotnick1*

Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, Oklahoma 73126-0901,1 Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037,2 Department of Microbiology and Immunology, Georgetown University Medical Center, 3900 Reservoir Rd. NW, Washington, DC 200073

Received 29 June 2008/ Accepted 30 July 2008

The relationship between the physical chemistry and biology of self-assembly is poorly understood, but it will be critical to quantitatively understand infection and for the design of antivirals that target virus genesis. Here we take advantage of heteroaryldihydropyrimidines (HAPs), which affect hepatitis B virus (HBV) assembly, to gain insight and correlate in vitro assembly with HBV replication in culture. Based on a low-resolution crystal structure of a capsid-HAP complex, a closely related series of HAPs were designed and synthesized. These differentially strengthen the association between neighboring capsid proteins, alter the kinetics of assembly, and give rise to aberrant structures incompatible with a functional capsid. The chemical nature of the HAP variants correlated well with the structure of the HAP binding pocket. The thermodynamics and kinetics of in vitro assembly had strong and predictable effects on product morphology. However, only the kinetics of in vitro assembly had a strong correlation with inhibition of HBV replication in HepG2.2.15 cells; there was at best a weak correlation between assembly thermodynamics and replication. The correlation between assembly kinetics and virus suppression implies a competition between successful assembly and misassembly, small molecule induced or otherwise. This is a predictive and testable model for the mechanism of action of assembly effectors.

* Corresponding author. Present address for Adam Zlotnick: Indiana University, Department of Biology, Simon Hall MSB, Room 220D, 212 S. Hawthorne Drive, Bloomington, IN 47405-7003. Phone: (812) 856-1925. Fax: (812) 856-5710. E-mail: azlotnic{at}indiana.edu. Mailing address for M. G. Finn: The Scripps Research Institute, Department of Chemistry, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-8845. Fax: (858) 784-8850. E-mail: mgfinn{at}scripps.edu

{triangledown} Published ahead of print on 6 August 2008.

{dagger} Present address: 250 McElroy Hall, Department of Veterinary Pathobiology, Oklahoma State University, Stillwater, OK 74078-2007.

Journal of Virology, October 2008, p. 10262-10270, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01360-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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