HIV integrase as a target for antiviral chemotherapy

Nair, Vasu

doi:10.1002/rmv.350

Cited by 49 publications

(41 citation statements)

References 59 publications

(71 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Antiretrovirals that act on alternative targets and that have more favorable safety profiles are urgently needed. Over the past decade advances in the understanding of HIV biology have revealed several new target sites for therapeutic intervention and have triggered the identification of several potential new antiretroviral agents including integrase inhibitors [6] and inhibitors of the HIV binding and entry process [7][8][9][10][11][12][13][14][15][16][17] (Table 1). The first of these to fulfill its potential is the fusion inhibitor enfuvirtide.…”

Section: Introductionmentioning

confidence: 99%

HIV fusion and its inhibition in antiretroviral therapy

Greenberg¹,

Cammack

Salgo

et al. 2004

Reviews in Medical Virology

View full text Add to dashboard Cite

The end of the twentieth century saw dramatic improvements in the prognosis of HIV infection brought about by the introduction of new agents (the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors) and their use in highly active combinations. However, the durability of these combination treatments is limited by a number of factors including adverse effects and extensive intra-class cross-resistance so that new antiretrovirals acting on alternative targets and having improved systemic tolerability profiles are required. The HIV binding and entry process offers several potential targets for antiviral interaction. These include gp120 binding to CD4 and to chemokine co-receptor molecules as well as the fusion process itself, which involves interactions between two leucine zipper-like 4-3 repeat regions within gp41 known as heptad repeat (HR)1 and HR2. Peptides such as enfuvirtide (formerly DP178 or T-20), that mimic the HR2 region of gp41, inhibit HIV-1 by a mechanism that is thought to involve competitive binding to HR1. This review summarises the clinical development of enfuvirtide, providing an overview of the pharmacokinetic, efficacy and safety data in various patient populations, and also considers the evidence for the key role of genotypic changes in the HR1 region (amino acids 36-45) in determining viral susceptibility to inhibition by enfuvirtide.

show abstract

Section: Introductionmentioning

confidence: 99%

HIV fusion and its inhibition in antiretroviral therapy

Greenberg¹,

Cammack

Salgo

et al. 2004

Reviews in Medical Virology

View full text Add to dashboard Cite

show abstract

“…Thus, integration of the viral genome into the cell's chromosome is a crucial step for completion of the HIV-1 life cycle, and its inhibition is an attractive target for anti-HIV drug development (32). By preventing integration, the anti-IN compounds preclude the subsequent steps of viral replication and spread while allowing the production of the extrachromosomal forms of viral DNA (E-DNA) (17,26,28,40,41). This recapitulates the effects obtained in cell cultures after infection with IN-defective viruses, which produce only E-DNA in the absence of integrated provirus (1,5,11).…”

mentioning

confidence: 99%

Development of a Human Immunodeficiency Virus Vector-Based, Single-Cycle Assay for Evaluation of Anti-Integrase Compounds

Bona

Andreotti

Buffa

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The development of chemotherapeutic agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection has focused primarily on two viral enzymes, reverse transcriptase (RT) and protease, and on the viral entry/fusion step (15, 31). Highly active antiretroviral therapy, consisting of multiple drug regimens attacking different targets and steps in the viral life cycle, has profoundly suppressed the levels of plasma viremia in patients infected with HIV-1, preventing opportunistic infections and reducing patient mortality. However, the emergence of multidrug-resistant variants remains problematic, suggesting the requirement for new antiviral agents (18,20). Integrase (IN) inhibitors, targeting a key enzyme of HIV-1 essential for its replication and persistence in the host genome, are one of the most promising classes of anti-HIV compounds. Importantly, two of them recently completed phase II clinical trials

show abstract

“…Many of the studies on inhibitors of HIV integrase have been done using radiolabelled assays with oligonucleotide substrates designed to mimic both the 3 0 P and ST processes [14][15][16]31,32]. The most active mononucleotides for inhibition of both the 3 0 P and DNA ST steps of HIV integrase (IC 50 40-70 mM) are L-ddCMP, L-5FddCMP and L5FddCTP [33].…”

Section: Earlier Studies Of Inhibitors Of Hiv Integrasementioning

confidence: 99%

“…Two of these enzymes, HIV reverse transcriptase and HIV protease, have received much attention in terms of the development of clinically useful inhibitors [4][5][6][7][8][9][10]. However, the third enzyme of the pol gene, HIV integrase [2,3,[11][12][13], has received relatively less attention in terms of inhibitors, in large part because of the difficulty associated with the discovery of therapeutically significant inhibitors [14][15][16]. There are no FDA-approved anti-HIV drugs in clinical use where the mechanism of action is inhibition of HIV integrase.…”

Section: Introductionmentioning

confidence: 99%

HIV integrase inhibitors as therapeutic agents in AIDS

Nair

Chi

2007

Reviews in Medical Virology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

HIV integrase as a target for antiviral chemotherapy

Cited by 49 publications

References 59 publications

HIV fusion and its inhibition in antiretroviral therapy

HIV fusion and its inhibition in antiretroviral therapy

Development of a Human Immunodeficiency Virus Vector-Based, Single-Cycle Assay for Evaluation of Anti-Integrase Compounds

HIV integrase inhibitors as therapeutic agents in AIDS

Contact Info

Product

Resources

About