Introducing ALZET?ew Model 2006 Pump Sign up for PNAS Online eTocs
Link: Info for AuthorsLink: Editorial BoardLink: AboutLink: SubscribeLink: AdvertiseLink: ContactLink: Sitemap Link: PNAS Home
Proceedings of the National Academy of Sciences
Link: Current Issue "" Link: Archives "" Link: Online Submission ""  Link: Advanced Search

Published online on May 31, 2005, 10.1073/pnas.0409732102
PNAS | June 7, 2005 | vol. 102 | no. 23 | 8138-8143


This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supporting Information
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stray, S. J.
Right arrow Articles by Zlotnick, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stray, S. J.
Right arrow Articles by Zlotnick, A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg  
What's this?

 Previous Article  | Table of Contents |  Next Article 

BIOCHEMISTRY
A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly

Stephen J. Stray *, Christina R. Bourne *, Sreenivas Punna {dagger}, Warren G. Lewis {dagger}, M. G. Finn {dagger}, and Adam Zlotnick *, {ddagger}

*Department of Biochemistry and Molecular Biology BRC 464, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK 73190; and {dagger}Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037

Edited by Jesse Summers, University of New Mexico, Albuquerque, NM and approved April 7, 2005 (received for review December 24, 2004)

Heteroaryldihydropyrimidines (HAPs) are a new class of antivirals inhibiting production of hepatitis B virus (HBV) virions in tissue culture. Here, we examine the effect of a representative HAP molecule, methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (HAP-1), on the in vitro assembly of HBV capsid protein (Cp). HAP-1 enhances the rate and extent of Cp assembly over a broad concentration range. Aberrant particles, dominated by hexagonal arrays of Cp, were observed from assembly reactions with high HAP-1 concentrations. HAP-1 also led to dissociation of metastable HBV capsids, overcoming a kinetic barrier to dissociation by scavenging Cp and redirecting its assembly into hexamer-rich structures. Thus, HAP drugs act as allosteric effectors that induce an assembly-active state and, at high concentration, preferentially stabilize noncapsid polymers of Cp. HAP compounds may have multiple effects in vivo stemming from inappropriate assembly of Cp. These results show that activating and deregulating virus assembly may be a powerful general approach for antiviral therapeutics.

antiviral | virus assembly | protein polymerization

Author contributions: S.J.S., M.G.F., and A.Z. designed research; S.J.S., C.R.B., S.P., and W.G.L. performed research; S.P., W.G.L., and M.G.F. contributed new reagents/analytic tools; S.J.S., C.R.B., M.G.F., and A.Z. analyzed data; and S.J.S. and A.Z. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: Cp, capsid protein; Cp149, Cp assembly domain (amino acids 1-149); HAP, heteroaryldihydropyrimidine; HAP-1, methyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate; HBV, hepatitis B virus; LS, light scattering; SEC, size-exclusion chromatography.

{ddagger} To whom correspondence should be addressed. E-mail: adam-zlotnick{at}ouhsc.edu.

© 2005 by The National Academy of Sciences of the USA


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg    What's this?


This article has been cited by other articles in HighWire Press-hosted journals:


Home page
 Biophys. JHome page
B. Sweeney, T. Zhang, and R. Schwartz
Exploring the Parameter Space of Complex Self-Assembly through Virus Capsid Models
Biophys. J., February 1, 2008; 94(3): 772 - 783.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
A. M. Dougherty, H. Guo, G. Westby, Y. Liu, E. Simsek, J.-T. Guo, A. Mehta, P. Norton, B. Gu, T. Block, et al.
A Substituted Tetrahydro-Tetrazolo-Pyrimidine Is a Specific and Novel Inhibitor of Hepatitis B Virus Surface Antigen Secretion
Antimicrob. Agents Chemother., December 1, 2007; 51(12): 4427 - 4437.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
C. R. Bourne, M. G. Finn, and A. Zlotnick
Global Structural Changes in Hepatitis B Virus Capsids Induced by the Assembly Effector HAP1
J. Virol., November 15, 2006; 80(22): 11055 - 11061.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
T. Zhang and R. Schwartz
Simulation Study of the Contribution of Oligomer/Oligomer Binding to Capsid Assembly Kinetics
Biophys. J., January 1, 2006; 90(1): 57 - 64.
[Abstract] [Full Text] [PDF]