Hiv integrase: a target for aids therapeutics

Thomas, Mark; Brady, Leo

doi:10.1016/s0167-7799(97)01016-0

Cited by 36 publications

(23 citation statements)

References 28 publications

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“…Thus, IN is well suited as a target for drug design, especially as no analogous host enzymes are known (15). No structural data on the binding of inhibitors, or even divalent cations, to HIV-1 IN have been published.…”

Section: Retroviral Integrase (In)mentioning

confidence: 99%

Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor

Łubkowski

Yang

Alexandratos

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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The Retroviral integrase (IN)ʈ catalyzes the integration of reversetranscribed viral DNA into the host genome in two steps called processing and joining (1-3). These reactions are chemically similar, proceeding via nucleophilic attack on the DNA by a donor hydroxyl group (water or ribose 3Ј OH), activated by the catalytic site of the enzyme. In vitro, these reactions require only divalent cations and water as cofactors. The in vitro reactions are fastest with Mn 2ϩ as the metal cofactor, although Mg 2ϩ also can be used. Because of its greater abundance in living cells, Mg 2ϩ is assumed to be the cofactor in vivo. Previous structural studies using the catalytic core domain of avian sarcoma virus (ASV) IN showed the presence of one cation of Mn 2ϩ or Mg 2ϩ

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Section: Retroviral Integrase (In)mentioning

confidence: 99%

Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor

Łubkowski

Yang

Alexandratos

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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“…18 and 19). IN has no cellular counterpart and can be therefore considered as a specific target for development of anti-HIV therapy (20). In an earlier study, we have reported (13) that Lys-159, a peptide corresponding to the 147-175 segment of HIV-1 IN, inhibited the integration catalyzed by IN, most likely through specific binding to its counterpart in the protein.…”

mentioning

confidence: 99%

Self-association and Domains of Interactions of an Amphipathic Helix Peptide Inhibitor of HIV-1 Integrase Assessed by Analytical Ultracentrifugation and NMR Experiments in Trifluoroethanol/H2O Mixtures

Maroun¹,

Krebs²,

Antri³

et al. 1999

Journal of Biological Chemistry

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EAA26 (VESMNEELKKIIAQVRAQAEHLKTAY) is a better inhibitor of human immunodeficiency virus, type1, integrase than its parent Lys-159, reproducing the enzyme segment 147-175 with a nonpolar-polar/charged residue periodicity defined by four helical heptads (abcdefg) prone to collapse into a coiled-coil. Circular dichroism, nuclear magnetic resonance, sedimentation equilibrium, and chemical cross-linking were used to analyze EAA26 in various trifluoroethanol/H 2 O mixtures. In pure water the helix content is weak but increases regularly up to 50 -60% trifluoroethanol. In contrast the multimerization follows a bell-shaped curve with monomers in pure water, tetramers at 10% trifluoroethanol, and dimers at 40% trifluoroethanol. All suggest that interhelical interactions between apolar side chains are required for the coiled-coil formation of EAA26 and subsist at medium trifluoroethanol concentration. The N H temperature coefficients measured by nuclear magnetic resonance show that at low trifluoroethanol concentration the amide groups buried in the hydrophobic interior of four ␣-helix bundles are weakly accessible to trifluoroethanol and are only weakly subject to its hydrogen bond strengthening effect. The increased accessibility of trifluoroethanol to buried amide groups at higher trifluoroethanol concentration entails the reduction of the hydrophobic interactions and the conversion of helix tetramers into helix dimers, the latter displaying a smaller hydrophobic interface. The better inhibitory activity of EAA26 compared with Lys-159 could arise from its better propensity to form a helix bundle structure with the biologically important helical part of the 147-175 segment in integrase.The well defined conformational properties exhibited by many peptides in solution have led to their use as models for protein folding and stability but also for the design of peptide inhibitors of enzymes (1-3). The model peptides are either artificial (4 -6) or may reproduce protein segments (7-13). When they have defined conformations, the peptides can provide useful information on the relationships between local interactions, secondary structures, and tertiary structures (14 -17).We have previously tested the hypothesis that synthetic peptides reproducing amphipathic helical segments of enzymes may interact with these segments and interfere with the catalytic properties. Examples concern topoisomerase II (10, 11), an enzyme involved in the maintenance of DNA topology, and also retroviral integrase (IN) 1 (12, 13) that catalyzes the integration of viral DNA into host cellular DNA (two recent reviews, Refs. 18 and 19). IN has no cellular counterpart and can be therefore considered as a specific target for development of anti-HIV therapy (20). In an earlier study, we have reported (13) that Lys-159, a peptide corresponding to the 147-175 segment of HIV-1 IN, inhibited the integration catalyzed by IN, most likely through specific binding to its counterpart in the protein. Such a specific binding was plausible since in the crystal struct...

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“…The IN-DNA complex is then transported into the nucleus where IN performs concerted integration of both viral DNA ends into host chromosomal DNA by a reaction referred to as strand transfer. The integration of viral DNA into host chromosomal DNA is essential for HIV-1 replication, making the inhibition of HIV-1 IN function an attractive antiviral strategy (9,35,36,42).Historically, treatment of individuals infected with HIV-1 has relied on agents targeting two of the viral enzymes, reverse transcriptase and protease. Despite important clinical results achieved through the use of combinations of these agents, the continuous emergence of drug resistance remains a significant problem which fuels the need to discover novel drugs targeting other steps of the HIV-1 life cycle.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase

Jones

Zeynalzadegan

et al. 2009

Antimicrob Agents Chemother

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GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) thatspecifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC 50 ) of ϳ2 nM, with a selectivity index (50% cytotoxic concentration/ EC 50 ) of ϳ2,000. The antiviral potency of GS-9160 decreased by 6-to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.After human immunodeficiency virus type 1 (HIV-1) entry and uncoating, the viral RNA is reverse transcribed by the viral reverse transcriptase into a double-stranded linear DNA. Both ends of this linear DNA are then processed at the 3Ј termini by the integrase (IN) enzyme. Specifically, IN removes a dinucleotide from each 3Ј terminus through a reaction referred to as 3Ј processing. The IN-DNA complex is then transported into the nucleus where IN performs concerted integration of both viral DNA ends into host chromosomal DNA by a reaction referred to as strand transfer. The integration of viral DNA into host chromosomal DNA is essential for HIV-1 replication, making the inhibition of HIV-1 IN function an attractive antiviral strategy (9,35,36,42).Historically, treatment of individuals infected with HIV-1 has relied on agents targeting two of the viral enzymes, reverse transcriptase and protease. Despite important clinical results achieved through the use of combinations of these agents, the continuous emergence of drug resistance remains a significant problem which fuels the need to discover novel drugs targeting other steps of the HIV-1 life cycle.

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Hiv integrase: a target for aids therapeutics

Cited by 36 publications

References 28 publications

Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor

Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor

Self-association and Domains of Interactions of an Amphipathic Helix Peptide Inhibitor of HIV-1 Integrase Assessed by Analytical Ultracentrifugation and NMR Experiments in Trifluoroethanol/H2O Mixtures

Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase

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