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Science 28 January 2000:
Vol. 287. no. 5453, pp. 646 - 650
DOI: 10.1126/science.287.5453.646
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Reports

Inhibitors of Strand Transfer That Prevent Integration and Inhibit HIV-1 Replication in Cells

Daria J. Hazuda, * Peter Felock, Marc Witmer, Abigail Wolfe, Kara Stillmock, Jay A. Grobler, Amy Espeseth, Lori Gabryelski, William Schleif, Carol Blau, Michael D. Miller

Integrase is essential for human immunodeficiency virus-type 1 (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. In this report, we describe diketo acid inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence of their effect on integration. The antiviral activity of these compounds is due exclusively to inhibition of one of the two catalytic functions of integrase, strand transfer.

Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA.
*   To whom correspondence should be addressed. E-mail: daria-hazuda{at}merck.com

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Homogeneous High-Throughput Screening Assays for HIV-1 Integrase 3{beta}-Processing and Strand Transfer Activities.
Y. Wang, H. Klock, H. Yin, K. Wolff, K. Bieza, K. Niswonger, J. Matzen, D. Gunderson, J. Hale, S. Lesley, et al. (2005)
J Biomol Screen 10, 456-462
   Abstract »    PDF »
Peptides Derived from the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 as Novel Inhibitors of the Viral Integrase.
I. Oz Gleenberg, O. Avidan, Y. Goldgur, A. Herschhorn, and A. Hizi (2005)
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Targeting Tn5 Transposase Identifies Human Immunodeficiency Virus Type 1 Inhibitors.
B. Ason, D. J. Knauss, A. M. Balke, G. Merkel, A. M. Skalka, and W. S. Reznikoff (2005)
Antimicrob. Agents Chemother. 49, 2035-2043
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Comparison of Multiple Molecular Dynamics Trajectories Calculated for the Drug-Resistant HIV-1 Integrase T66I/M154I Catalytic Domain.
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Pre-organized structure of viral DNA at the binding-processing site of HIV-1 integrase.
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Mass Spectrometric Analysis of the HIV-1 Integrase-Pyridoxal 5'-Phosphate Complex Reveals a New Binding Site for a Nucleotide Inhibitor.
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Nef expressed from human immunodeficiency virus type 1 extrachromosomal DNA downregulates CD4 on primary CD4+ T lymphocytes: implications for integrase inhibitors.
L. Gillim-Ross, A. Cara, and M. E. Klotman (2005)
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HIV-1 integrase crosslinked oligomers are active in vitro.
A.él. Faure, C. Calmels, Céc. Desjobert, M. Castroviejo, A. Caumont-Sarcos, L. Tarrago-Litvak, S. Litvak, and V. Parissi (2005)
Nucleic Acids Res. 33, 977-986
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Kinetics of Human Immunodeficiency Virus Type 1 Decay following Entry into Resting CD4+ T Cells.
Y. Zhou, H. Zhang, J. D. Siliciano, and R. F. Siliciano (2005)
J. Virol. 79, 2199-2210
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Genetic Analyses of DNA-Binding Mutants in the Catalytic Core Domain of Human Immunodeficiency Virus Type 1 Integrase.
R. Lu, A. Limon, H. Z. Ghory, and A. Engelman (2005)
J. Virol. 79, 2493-2505
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Identification of an Evolutionarily Conserved Domain in Human Lens Epithelium-derived Growth Factor/Transcriptional Co-activator p75 (LEDGF/p75) That Binds HIV-1 Integrase.
P. Cherepanov, E. Devroe, P. A. Silver, and A. Engelman (2004)
J. Biol. Chem. 279, 48883-48892
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Nuclear Import of HIV-1 Integrase Is Inhibited in Vitro by Styrylquinoline Derivatives.
A. Mousnier, H. Leh, J.-F. Mouscadet, and C. Dargemont (2004)
Mol. Pharmacol. 66, 783-788
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From the Cover: A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase.
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PNAS 101, 11233-11238
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Integrase Inhibitors and Cellular Immunity Suppress Retroviral Replication in Rhesus Macaques.
D. J. Hazuda, S. D. Young, J. P. Guare, N. J. Anthony, R. P. Gomez, J. S. Wai, J. P. Vacca, L. Handt, S. L. Motzel, H. J. Klein, et al. (2004)
Science 305, 528-532
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Detection of Human Immunodeficiency Virus Type 1 Antiretroviral Resistance Mutations by High-Density DNA Probe Arrays.
R. Gonzalez, B. Masquelier, H. Fleury, B. Lacroix, A. Troesch, G. Vernet, and J. N. Telles (2004)
J. Clin. Microbiol. 42, 2907-2912
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A high-throughput assay for Tn5 Tnp-induced DNA cleavage.
B. Ason and W. S. Reznikoff (2004)
Nucleic Acids Res. 32, e83
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Styrylquinolines, Integrase Inhibitors Acting Prior to Integration: a New Mechanism of Action for Anti-Integrase Agents.
S. Bonnenfant, C. M. Thomas, C. Vita, F. Subra, E. Deprez, F. Zouhiri, D. Desmaele, J. d'Angelo, J. F. Mouscadet, and H. Leh (2004)
J. Virol. 78, 5728-5736
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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.
D. J. Lee and W. E. Robinson Jr. (2004)
J. Virol. 78, 5835-5847
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Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry.
N. Shkriabai, S. S. Patil, S. Hess, S. R. Budihas, R. Craigie, T. R. Burke Jr., S. F. J. Le Grice, and M. Kvaratskhelia (2004)
PNAS 101, 6894-6899
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Structural Organization of Avian Retrovirus Integrase in Assembled Intasomes Mediating Full-site Integration.
A. Vora, S. Bera, and D. Grandgenett (2004)
J. Biol. Chem. 279, 18670-18678
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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.
E. S. Svarovskaia, R. Barr, X. Zhang, G. C. G. Pais, C. Marchand, Y. Pommier, T. R. Burke Jr., and V. K. Pathak (2004)
J. Virol. 78, 3210-3222
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HIV Drug Resistance.
F. Clavel and A. J. Hance (2004)
N. Engl. J. Med. 350, 1023-1035
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Biochemical and random mutagenesis analysis of the region carrying the catalytic E152 amino acid of HIV-1 integrase.
C. Calmels, V. R. de Soultrait, A. Caumont, C. Desjobert, A. Faure, M. Fournier, L. Tarrago-Litvak, and V. Parissi (2004)
Nucleic Acids Res. 32, 1527-1538
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Simian Virus 40-Based Replication of Catalytically Inactive Human Immunodeficiency Virus Type 1 Integrase Mutants in Nonpermissive T Cells and Monocyte-Derived Macrophages.
R. Lu, N. Nakajima, W. Hofmann, M. Benkirane, K. Teh-Jeang, J. Sodroski, and A. Engelman (2004)
J. Virol. 78, 658-668
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Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro.
E. Deprez, S. Barbe, M. Kolaski, H. Leh, F. Zouhiri, C. Auclair, J.-C. Brochon, M. Le Bret, and J.-F. Mouscadet (2004)
Mol. Pharmacol. 65, 85-98
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Development of Resistance against Diketo Derivatives of Human Immunodeficiency Virus Type 1 by Progressive Accumulation of Integrase Mutations.
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. (2003)
J. Virol. 77, 11459-11470
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Discovery of a Small Molecule Tat-trans-Activation-responsive RNA Antagonist That Potently Inhibits Human Immunodeficiency Virus-1 Replication.
S. Hwang, N. Tamilarasu, K. Kibler, H. Cao, A. Ali, Y.-H. Ping, K.-T. Jeang, and T. M. Rana (2003)
J. Biol. Chem. 278, 39092-39103
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Early Transcription from Nonintegrated DNA in Human Immunodeficiency Virus Infection.
Y. Wu and J. W. Marsh (2003)
J. Virol. 77, 10376-10382
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Metal-Dependent Inhibition of HIV-1 Integrase by {beta}-Diketo Acids and Resistance of the Soluble Double-Mutant (F185K/C280S).
C. Marchand, A. A. Johnson, R. G. Karki, G. C. G. Pais, X. Zhang, K. Cowansage, T. A. Patel, M. C. Nicklaus, T. R. Burke Jr., and Y. Pommier (2003)
Mol. Pharmacol. 64, 600-609
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Strategy to Discriminate between High and Low Affinity Bindings of Human Immunodeficiency Virus, Type 1 Integrase to Viral DNA.
L. Zargarian, M. S. Benleumi, J.-G. Renisio, H. Merad, R. G. Maroun, F. Wieber, O. Mauffret, H. Porumb, F. Troalen, and S. Fermandjian (2003)
J. Biol. Chem. 278, 19966-19973
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Impact of the Central Polypurine Tract on the Kinetics of Human Immunodeficiency Virus Type 1 Vector Transduction.
B. Van Maele, J. De Rijck, E. De Clercq, and Z. Debyser (2003)
J. Virol. 77, 4685-4694
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Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response.
R. Daniel, G. Kao, K. Taganov, J. G. Greger, O. Favorova, G. Merkel, T. J. Yen, R. A. Katz, and A. M. Skalka (2003)
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Molecular Dynamics Studies of the Wild-Type and Double Mutant HIV-1 Integrase Complexed with the 5CITEP Inhibitor: Mechanism for Inhibition and Drug Resistance.
M. L. Barreca, K. W. Lee, A. Chimirri, and J. M. Briggs (2003)
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Inhibition of HIV-1 Ribonuclease H by a Novel Diketo Acid, 4-[5-(Benzoylamino)thien-2-yl]-2,4-dioxobutanoic Acid.
C. A. Shaw-Reid, V. Munshi, P. Graham, A. Wolfe, M. Witmer, R. Danzeisen, D. B. Olsen, S. S. Carroll, M. Embrey, J. S. Wai, et al. (2003)
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   Abstract »    Full Text »    PDF »
Human Immunodeficiency Virus Hematology.
P. A. Volberding, K. R. Baker, and A. M. Levine (2003)
Hematology 2003, 294-313
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A Sensitive, Quantitative Assay for Human Immunodeficiency Virus Type 1 Integration.
U. O'Doherty, W. J. Swiggard, D. Jeyakumar, D. McGain, and M. H. Malim (2002)
J. Virol. 76, 10942-10950
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Inhibition of Human Immunodeficiency Virus Type 1 Integration by Diketo Derivatives.
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 (2002)
Antimicrob. Agents Chemother. 46, 3292-3297
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Inhibition of Human Immunodeficiency Virus Type 1 Isolates by the Integrase Inhibitor L-731,988, a Diketo Acid.
R. Reinke, D. J. Lee, and W. E. Robinson Jr. (2002)
Antimicrob. Agents Chemother. 46, 3301-3303
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Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes.
J. A. Grobler, K. Stillmock, B. Hu, M. Witmer, P. Felock, A. S. Espeseth, A. Wolfe, M. Egbertson, M. Bourgeois, J. Melamed, et al. (2002)
PNAS 99, 6661-6666
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Structural Determinants for HIV-1 Integrase Inhibition by beta -Diketo Acids.
C. Marchand, X. Zhang, G. C. G. Pais, K. Cowansage, N. Neamati, T. R. Burke Jr., and Y. Pommier (2002)
J. Biol. Chem. 277, 12596-12603
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Intrinsic Stability of Episomal Circles Formed during Human Immunodeficiency Virus Type 1 Replication.
T. C. Pierson, T. L. Kieffer, C. T. Ruff, C. Buck, S. J. Gange, and R. F. Siliciano (2002)
J. Virol. 76, 4138-4144
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Effect of HIV integrase inhibitors on the RAG1/2 recombinase.
M. Melek, J. M. Jones, M. H. O'Dea, G. Pais, T. R. Burke Jr., Y. Pommier, N. Neamati, and M. Gellert (2001)
PNAS
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HIV-1 Preintegration Complexes Preferentially Integrate into Longer Target DNA Molecules in Soluti