Azido‐Containing Aryl β‐Diketo Acid HIV‐1 Integrase Inhibitors.

Zhang, Xuechun; Pais, Godwin C. G.; Svarovskaia, Evguenia S.; Marchand, Christophe; Johnson, Allison A.; Karki, Rajeshri G.; Nicklaus, Marc C.; Pathak, Vinay Kumar; Pommier, ﻿Yves; Burke, Terrence R.

doi:10.1002/chin.200329076

Cited by 13 publications

(18 citation statements)

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“…Modeling of the azido-containing and benzyloxy-containing DKAs indicates that they are essentially superimposable, but the benzyloxy groups occupy more space (70). Interestingly, recent modeling studies have indicated that the azido-containing DKAs might bind to the active site of HIV-1 IN in two different modes: in addition to binding to HIV-1 IN in a manner similar to that of L-708,906, another mode of binding could take place in which the azido moiety, rather than the diketo moiety, participates in metal chelation (45).…”

Section: Discussionmentioning

confidence: 99%

“…In these studies, DKAs that contained one or two azido moieties exhibited potent and selective inhibition of the strand transfer reaction catalyzed by HIV-1 IN (46,70). The structures of the previously reported DKA L-708,906 (31), another structurally related benzyloxy-containing DKA (MB-DKA), and two azido-containing DKAs (DA-DKA and MA-DKA) are shown in Fig.…”

Section: Structures Of Azido-containing Dkas That Inhibit Hiv-1 Inmentioning

confidence: 90%

“…We recently synthesized a series of DKA derivatives and determined their abilities to inhibit HIV-1 IN in an in vitro assay (53,70). In these studies, DKAs that contained one or two azido moieties exhibited potent and selective inhibition of the strand transfer reaction catalyzed by HIV-1 IN (46,70).…”

Section: Structures Of Azido-containing Dkas That Inhibit Hiv-1 Inmentioning

confidence: 99%

“…Recently, we described azido-group-containing DKAs that potently inhibit the strand transfer reaction catalyzed by HIV-1 IN (45,70). In the present study, we have further evaluated the antiviral activity of these compounds and analyzed their intracellular mechanism of action.…”

mentioning

confidence: 94%

“…␤-Diketo acid derivatives (DKAs) are potent inhibitors of HIV-1 integration in vitro and in vivo (3,31,45,53,70). High-throughput screening assays were performed to identify DKAs such as L-708,906 that are selective and potent inhibitors of the strand transfer reaction catalyzed by HIV-1 IN (31).…”

mentioning

confidence: 99%

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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

Svarovskaia

Barr

Zhang

et al. 2004

J Virol

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Section: Discussionmentioning

confidence: 99%

Section: Structures Of Azido-containing Dkas That Inhibit Hiv-1 Inmentioning

confidence: 90%

Section: Structures Of Azido-containing Dkas That Inhibit Hiv-1 Inmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

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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

Svarovskaia

Barr

Zhang

et al. 2004

J Virol

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A targeted DNA substrate mechanism for the inhibition of HIV‐1 integrase by inhibitors with antiretroviral activity

et al. 2016

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We recently reported that viral DNA could be the primary target of raltegravir ( RAL ), an efficient anti‐ HIV ‐1 drug, which acts by inhibiting integrase. To elucidate this mechanism, we conducted a comparative analysis of RAL and TB 11, a diketoacid abandoned as an anti‐ HIV ‐1 drug for its weak efficiency and marked toxicity, and tested the effects of the catalytic cofactor Mg 2+ (5 m m ) on drug‐binding properties. We used circular dichroism and fluorescence to determine drug affinities for viral DNA long terminal repeats ( LTR s) and peptides derived from the integrase active site and DNA retardation assays to assess drug intercalation into DNA base pairs. We found that RAL bound more tightly to LTR ends than did TB 11 (a diketo acid bearing an azido group) and that Mg 2+ significantly increased the affinity of both RAL and TB 11. We also observed a good relationship between drug binding with processed LTR and strand transfer inhibition. This unusual type of inhibition was caused by Mg 2+ ‐assisted binding of drugs to DNA substrate, rather than to enzyme. Notably, while RAL bound exclusively to the cleavable/cleaved site, TB 11 further intercalated into DNA base pairs and interacted with the integrase‐derived peptides. These unwanted binding sites explain the weaker bioavailability and higher toxicity of TB 11 compared with the more effective RAL .

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HIV‐1 integrase inhibitors: 2003–2004 update

Dayam

Deng

Neamati

2006

Medicinal Research Reviews

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The integration of viral cDNA into the host genome is an essential step in the HIV-1-life cycle and is mediated by the virally encoded enzyme, integrase (IN). Inhibition of this process provides an attractive strategy for antiviral drug design. The discovery of beta-diketo acid inhibitors played a major role in validating IN as a legitimate antiretroviral drug target. Over a decade of research, a plethora of IN inhibitors have been discovered and some showed antiviral activity consistent with their effect on IN. To date, at least two compounds have been tested in human but none are close to the FDA approval. In this review, we provide a comprehensive report of all small-molecule IN inhibitors discovered during the years 2003 and 2004. Compilation of such data will prove beneficial in developing QSAR, virtual screening, pharmacophore hypothesis generation, and validation.

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Azido‐Containing Aryl β‐Diketo Acid HIV‐1 Integrase Inhibitors.

Cited by 13 publications

References 1 publication

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

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

A targeted DNA substrate mechanism for the inhibition of HIV‐1 integrase by inhibitors with antiretroviral activity

HIV‐1 integrase inhibitors: 2003–2004 update

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