This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sakalian, M.
Right arrow Articles by Salzwedel, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sakalian, M.
Right arrow Articles by Salzwedel, K.

 Previous Article  |  Next Article 

Journal of Virology, June 2006, p. 5716-5722, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02743-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

3-O-(3',3'-Dimethysuccinyl) Betulinic Acid Inhibits Maturation of the Human Immunodeficiency Virus Type 1 Gag Precursor Assembled In Vitro

Michael Sakalian,1* Curtis P. McMurtrey,1 Frederick J. Deeg,1 Christopher W. Maloy,1 Feng Li,2 Carl T. Wild,2,{dagger} and Karl Salzwedel2

Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104,1 Panacos Pharmaceuticals, Inc., 209 Perry Parkway, Gaithersburg, Maryland 208772

Received 30 December 2005/ Accepted 23 March 2006

3-O-(3',3'-Dimethysuccinyl) betulinic acid (PA-457) has been shown to potently inhibit human immunodeficiency virus (HIV) replication in culture. In contrast to inhibitors that act upon the viral proteinase, PA-457 appears to block only the final maturational cleavage of p25CA-p2 to p24CA. However, attempts to replicate this effect in vitro using recombinant Gag have failed, leading to the hypothesis that activity is dependent upon the assembly state of Gag. Using a synthesis/assembly system for chimeric HIV type 1 Gag proteins, we have replicated the activity of PA-457 in vitro. The processing of assembled chimeric Gag can be inhibited by the addition of drug with only the final cleavage of p25CA-p2 to p24CA blocked. Consistent with our hypothesis and with previous findings, inhibition appears specific to Gag assembled into an immature capsid-like structure, since synthetic Gag that remains unassembled is properly processed in the presence of the compound. To further analyze the authenticity of the assay, PA-457 was tested in parallel with its inactive parental compound, betulinic acid. Betulinic acid had no effect upon p25 processing in this system. Analysis of a PA-457-resistant mutant, A1V, in this system pointed to more rapid cleavage as a possible mechanism for resistance. However, characterization of additional mutations at the cleavage site and in p2 suggests that resistance does not strictly correlate with the rate of cleavage. With the establishment of an in vitro assay for the detection of PA-457 activity, a more detailed characterization of its mechanism of action will be possible.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, BMSB 1019, 940 Stanton L. Young Boulevard, Oklahoma City, OK 73104. Phone: (405) 271-2133. Fax: (405) 271-3117. E-mail: mike-sakalian{at}ouhsc.edu.

{dagger} Present address: 19008 Oxcart Place, Gaithersburg, MD 20886.

Journal of Virology, June 2006, p. 5716-5722, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02743-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Blair, W. S., Cao, J., Fok-Seang, J., Griffin, P., Isaacson, J., Jackson, R. L., Murray, E., Patick, A. K., Peng, Q., Perros, M., Pickford, C., Wu, H., Butler, S. L. (2009). New Small-Molecule Inhibitor Class Targeting Human Immunodeficiency Virus Type 1 Virion Maturation. Antimicrob. Agents Chemother. 53: 5080-5087 [Abstract] [Full Text]  
  • Adamson, C. S., Waki, K., Ablan, S. D., Salzwedel, K., Freed, E. O. (2009). Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457). J. Virol. 83: 4884-4894 [Abstract] [Full Text]  
  • Van Baelen, K., Salzwedel, K., Rondelez, E., Van Eygen, V., De Vos, S., Verheyen, A., Steegen, K., Verlinden, Y., Allaway, G. P., Stuyver, L. J. (2009). Susceptibility of Human Immunodeficiency Virus Type 1 to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag Spacer Peptide 1. Antimicrob. Agents Chemother. 53: 2185-2188 [Abstract] [Full Text]  
  • Keller, P. W., Johnson, M. C., Vogt, V. M. (2008). Mutations in the Spacer Peptide and Adjoining Sequences in Rous Sarcoma Virus Gag Lead to Tubular Budding. J. Virol. 82: 6788-6797 [Abstract] [Full Text]  
  • Purdy, J. G., Flanagan, J. M., Ropson, I. J., Rennoll-Bankert, K. E., Craven, R. C. (2008). Critical Role of Conserved Hydrophobic Residues within the Major Homology Region in Mature Retroviral Capsid Assembly. J. Virol. 82: 5951-5961 [Abstract] [Full Text]  
  • Zhou, J., Chen, C. H., Aiken, C. (2006). Human Immunodeficiency Virus Type 1 Resistance to the Small Molecule Maturation Inhibitor 3-O-(3',3'-Dimethylsuccinyl)-Betulinic Acid Is Conferred by a Variety of Single Amino Acid Substitutions at the CA-SP1 Cleavage Site in Gag. J. Virol. 80: 12095-12101 [Abstract] [Full Text]  
  • Adamson, C. S., Ablan, S. D., Boeras, I., Goila-Gaur, R., Soheilian, F., Nagashima, K., Li, F., Salzwedel, K., Sakalian, M., Wild, C. T., Freed, E. O. (2006). In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat). J. Virol. 80: 10957-10971 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»