HIV Integrase Inhibitors with Nucleobase Scaffolds:  Discovery of a Highly Potent Anti-HIV Agent

Nair, Vasu; Chi, Guochen; Ptak, Roger G.; Neamati, Nouri

doi:10.1021/jm0508890

Cited by 69 publications

(42 citation statements)

References 29 publications

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“…56 Figure 15) [112,120] were cytotoxic. In keeping with the indole DKAs, purine (57 & 58, Figure 16) 121 and pyrimidine (59 & 60) [122] analogues displayed potent in vitro activity, reduced in vivo activity and reduced strand-transfer selectivity. However, the reduction of selectivity of these analogues is not expected as they mimic the natural substrate.…”

Section: Polyhydroxylated Aromatic Hiv-1 Inhibitorsmentioning

confidence: 69%

Control of HIV Through the Inhibition of HIV-1 Integrase: A Medicinal Chemistry Perspective

Gordon¹,

Griffith

Keller

2007

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This article reviews the current status of classes of HIV-1 integrase enzyme inhibitors. These classes include peptide-based inhibitors, natural products, polyhydroxylated aromatics, diketo acids, naphthyridines, and sulfonated compounds including sulfonic acids. Discussions of structure activity relationships are presented and include the current overview of the structure-based model, suitable for the further design and development. To date, the advances in the medicinal chemistry of HIV-1 integrase inhibitors have relied mostly on ligand-based designs leading to most displaying similar binding interactions within the active site or at the dimer interface. This paves the way for single enzyme mutations rendering entire compound classes inactive and thus, the requirement for second and third generation inhibitors with novel modes of binding is apparent. To facilitate future structure-based drug design efforts, a model of the biologically relevant structure of the HIV-1 integrase enzyme, a dimmer of dimmers has also been discussed. AbstractThis article reviews the current status of classes of HIV-1 integrase enzyme inhibitors. These classes include peptide-based inhibitors, natural products, polyhydroxylated aromatics, diketo acids, naphthyridines, and sulfonated compounds including sulfonic acids. Discussions of structure activity relationships are presented and include the current overview of the structure-based model, suitable for the further design and development. To date, the advances in the medicinal chemistry of HIV-1 integrase inhibitors have relied mostly on ligand-based designs leading to most displaying similar binding interactions within the active site or at the dimer interface. This paves the way for single enzyme mutations rendering entire compound classes inactive and thus, the requirement for second and third generation inhibitors with novel modes of binding is apparent. To facilitate future structure-based drug design efforts, a model of the biologically relevant structure of the HIV-1 integrase enzyme, a dimmer of dimmers has also been discussed.

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Section: Polyhydroxylated Aromatic Hiv-1 Inhibitorsmentioning

confidence: 69%

Control of HIV Through the Inhibition of HIV-1 Integrase: A Medicinal Chemistry Perspective

Gordon¹,

Griffith

Keller

2007

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“…In our laboratory, we discovered conceptually new -diketo acids with nucleobase scaffolds that are potent inhibitors of both the 3 0 P and ST steps of HIV integrase [63][64][65][66][67]. Our data suggest that the nucleobase scaffold, the substituents and the specific spatial relationship of substituents in the scaffold, are critical for potent integrase inhibitory activity.…”

Section: Diketo Acids With Nucleobase Scaffoldsmentioning

confidence: 90%

HIV integrase inhibitors as therapeutic agents in AIDS

Nair

Chi

2007

Reviews in Medical Virology

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HIV-1 integrase is a protein of Mr 32 000 encoded at the 3'-end of the pol gene. Integration of HIV DNA into the host cell chromosomal DNA apparently occurs by a carefully defined sequence of DNA tailoring (3'-processing (3'P)) and coupling (integration) reactions. Integration of HIV DNA into human DNA represents the biochemical completion of the invasion of the human cell (e.g., T-cell) by HIV. Unlike major successes seen in the development of clinically approved anti-HIV agents against HIV reverse transcriptase and HIV protease, there are no FDA-approved anti-HIV drugs in clinical use where the mechanism of action is inhibition of HIV integrase. This review summarises some key advances in the area of integrase inhibitors with the major focus being on new generation inhibitors. Special emphasis is placed on diketo acids with aromatic and heteroaromatic moieties, diketo acids with nucleobase scaffolds, bis-diketo acids, functionalised naphthyridines and other isosteres of diketo acids. Data pertaining to integrase inhibition and in vitro anti-HIV activity are discussed. Mention is made of drugs in clinical trials, both past (S-1360, L-870,810 and L-870,812 and present (GS-9137 and MK-0518). Other promising drugs, including those from the authors' laboratory, are referred. Resistant mutants arising from key integrase inhibitors and cross-resistance are indicated.

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“…Nair et al reported that bis-benzylated nucleobase with a -diketo acids are potent HIV integrase inhibitors [12].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti‐HIV‐1 evaluation of 1,5‐disubstituted pyrimidine‐2,4‐diones

Loksha

Globisch

Pedersen

et al. 2008

Journal of Heterocyclic Chem

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HIV Integrase Inhibitors with Nucleobase Scaffolds: Discovery of a Highly Potent Anti-HIV Agent

Cited by 69 publications

References 29 publications

Control of HIV Through the Inhibition of HIV-1 Integrase: A Medicinal Chemistry Perspective

Control of HIV Through the Inhibition of HIV-1 Integrase: A Medicinal Chemistry Perspective

HIV integrase inhibitors as therapeutic agents in AIDS

Synthesis and anti‐HIV‐1 evaluation of 1,5‐disubstituted pyrimidine‐2,4‐diones

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