MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
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
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pluymers, W.
Right arrow Articles by Witvrouw, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pluymers, W.
Right arrow Articles by Witvrouw, M.

Vol. 58, Issue 3, 641-648, September 2000

Viral Entry as the Primary Target for the Anti-HIV Activity of Chicoric Acid and Its Tetra-Acetyl Esters

Wim Pluymers, Nouri Neamati, Christophe Pannecouque, Valery Fikkert, Christophe Marchand, Terrence R. Burke, Jr., Yves Pommier, Dominique Schols, Erik De Clercq, Zeger Debyser, and Myriam Witvrouw

Rega Institute for Medical Research, K. U. Leuven, Leuven, Belgium (W.P., C.P., V.F., D.S., E.D.C., Z.D., M.W.); Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland (N.N., C.M., T.R.B., Y.P.).

The antiviral activity of L-chicoric acid against HIV-1 has been attributed previously to the inhibition of HIV-1 integration. This conclusion was based on the inhibition of integrase activity in enzymatic assays and the isolation of a resistant HIV strain with a mutation (G140S) in the integrase gene. Here we show that the primary antiviral target of L-CA and its analogs in cell culture is viral entry. L- and D-chicoric acid (L-CA and D-CA) and their respective tetra-acetyl esters inhibit the replication of HIV-1 (IIIB and NL4.3) and HIV-2 (ROD) in MT-4 cells at a 50% effective concentration (EC50) ranging from 1.7 to 70.6 µM. In a time-of-addition experiment, L-CA, D-CA, L-CATA, and D-CATA were found to interfere with an early event in the viral replication cycle. Moreover, L-CA, D-CA, and their analogs did not inhibit the replication of virus strains that were resistant toward polyanionic and polycationic compounds at subtoxic concentrations. Furthermore, HIV-1 strains resistant to L-CA and D-CA were selected in the presence of L-CA and D-CA, respectively. Mutations were found in the V2, V3, and V4 loop region of the envelope glycoprotein gp120 of the L-CA and D-CA-resistant NL4.3 strains that were not present in the wild-type NL4.3 strain. Recombination of the gp120 gene of the L-CA and D-CA resistant strain in a NL4.3 wild-type molecular clone fully rescued the phenotypic resistance toward L-CA and D-CA. No significant mutations were detected in the integrase gene of the drug-resistant virus strains. Although inhibition of HIV integrase activity by L-CA and its derivatives was confirmed in an oligonucleotide-driven assay, integrase carrying the G140S mutation was inhibited to the same extent as the wild-type integrase.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Antimicrob. Agents Chemother.Home page
A. Hombrouck, B. Van Remoortel, M. Michiels, W. Noppe, F. Christ, A. Eneroth, B. L. Sahlberg, K. Benkestock, L. Vrang, N. G. Johansson, et al.
Preclinical Evaluation of 1H-Benzylindole Derivatives as Novel Human Immunodeficiency Virus Integrase Strand Transfer Inhibitors
Antimicrob. Agents Chemother., August 1, 2008; 52(8): 2861 - 2869.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
A. Hombrouck, A. Hantson, B. van Remoortel, M. Michiels, J. Vercammen, D. Rhodes, V. Tetz, Y. Engelborghs, F. Christ, Z. Debyser, et al.
Selection of human immunodeficiency virus type 1 resistance against the pyranodipyrimidine V-165 points to a multimodal mechanism of action
J. Antimicrob. Chemother., June 1, 2007; 59(6): 1084 - 1095.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
D. Daelemans, R. Lu, E. De Clercq, and A. Engelman
Characterization of a Replication-Competent, Integrase-Defective Human Immunodeficiency Virus (HIV)/Simian Virus 40 Chimera as a Powerful Tool for the Discovery and Validation of HIV Integrase Inhibitors
J. Virol., April 15, 2007; 81(8): 4381 - 4385.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
S. Kehlenbeck, U. Betz, A. Birkmann, B. Fast, A. H. Goller, K. Henninger, T. Lowinger, D. Marrero, A. Paessens, D. Paulsen, et al.
Dihydroxythiophenes Are Novel Potent Inhibitors of Human Immunodeficiency Virus Integrase with a Diketo Acid-Like Pharmacophore
J. Virol., July 15, 2006; 80(14): 6883 - 6894.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
B. Ason, D. J. Knauss, A. M. Balke, G. Merkel, A. M. Skalka, and W. S. Reznikoff
Targeting Tn5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors
Antimicrob. Agents Chemother., May 1, 2005; 49(5): 2035 - 2043.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
J. Balzarini, K. Van Laethem, S. Hatse, K. Vermeire, E. De Clercq, W. Peumans, E. Van Damme, A.-M. Vandamme, A. Bohlmstedt, and D. Schols
Profile of Resistance of Human Immunodeficiency Virus to Mannose-Specific Plant Lectins
J. Virol., October 1, 2004; 78(19): 10617 - 10627.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
S. Bonnenfant, C. M. Thomas, C. Vita, F. Subra, E. Deprez, F. Zouhiri, D. Desmaele, J. d'Angelo, J. F. Mouscadet, and H. Leh
Styrylquinolines, Integrase Inhibitors Acting Prior to Integration: a New Mechanism of Action for Anti-Integrase Agents
J. Virol., June 1, 2004; 78(11): 5728 - 5736.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
D. J. Lee and W. E. Robinson Jr.
Human Immunodeficiency Virus Type 1 (HIV-1) Integrase: Resistance to Diketo Acid Integrase Inhibitors Impairs HIV-1 Replication and Integration and Confers Cross-Resistance to L-Chicoric Acid
J. Virol., June 1, 2004; 78(11): 5835 - 5847.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
N. Shkriabai, S. S. Patil, S. Hess, S. R. Budihas, R. Craigie, T. R. Burke Jr., S. F. J. Le Grice, and M. Kvaratskhelia
Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry
PNAS, May 4, 2004; 101(18): 6894 - 6899.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
E. S. Svarovskaia, R. Barr, X. Zhang, G. C. G. Pais, C. Marchand, Y. Pommier, T. R. Burke Jr., and V. K. Pathak
Azido-Containing Diketo Acid Derivatives Inhibit Human Immunodeficiency Virus Type 1 Integrase In Vivo and Influence the Frequency of Deletions at Two-Long-Terminal-Repeat-Circle Junctions
J. Virol., April 1, 2004; 78(7): 3210 - 3222.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
V. Fikkert, B. Van Maele, J. Vercammen, A. Hantson, B. Van Remoortel, M. Michiels, C. Gurnari, C. Pannecouque, M. De Maeyer, Y. Engelborghs, et al.
Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase Mutations
J. Virol., November 1, 2003; 77(21): 11459 - 11470.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
B. Van Maele, J. De Rijck, E. De Clercq, and Z. Debyser
Impact of the Central Polypurine Tract on the Kinetics of Human Immunodeficiency Virus Type 1 Vector Transduction
J. Virol., April 15, 2003; 77(8): 4685 - 4694.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
W. Pluymers, G. Pais, B. Van Maele, C. Pannecouque, V. Fikkert, T. R. Burke Jr., E. De Clercq, M. Witvrouw, N. Neamati, and Z. Debyser
Inhibition of Human Immunodeficiency Virus Type 1 Integration by Diketo Derivatives
Antimicrob. Agents Chemother., October 1, 2002; 46(10): 3292 - 3297.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
E. De Clercq
Molecular Targets for Antiviral Agents
J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 1 - 10.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics