Anti-infectives Clinical progress of HIV-1 integrase inhibitors

Al‐Mawsawi, Laith Q.; Al-Safi, Rasha I.; Neamati, Nouri

doi:10.1517/14728214.13.2.213

Cited by 49 publications

(43 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Over a decade of these drug design efforts has led to the discovery of the strand transfer-specific class of small molecule IN inhibitors, with three compounds demonstrating clinical success (4,5). One IN strand transfer inhibitor (INSTI), raltegravir (MK-0518), was approved by the FDA in 2007 for the treatment of HIV-1 infection (6 -8), and a second INSTI, elvitegravir (GS-9137), which is in late-stage clinical development, is dosed once daily with a new pharmacokinetic enhancer, cobicistat (9 -11).…”

mentioning

confidence: 99%

New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

Tsiang

Jones

Niedziela-Majka

et al. 2012

Journal of Biological Chemistry

149

259

View full text Add to dashboard Cite

Background:Competitors of LEDGF binding to HIV-1 integrase could prevent targeted integration to chromatin. Results: LEDGF competitors like tBPQAs were also found to inhibit integrase enzyme activity by preventing proper integraseviral DNA assembly. Conclusion: tBPQAs are allosteric inhibitors of integrase with a dual mode of action. Significance: Interference with two distinct steps of integration through the same binding site represents a new antiviral paradigm.

show abstract

mentioning

confidence: 99%

New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

Tsiang

Jones

Niedziela-Majka

et al. 2012

Journal of Biological Chemistry

149

259

View full text Add to dashboard Cite

show abstract

“…The latter is an essential and irreversible event which is mediated by the catalytic activities of the viral integrase protein (IN), the recent target of successful chemotherapeutic intervention against HIV-1 infection (1). HIV-1 IN is a 288-amino-acid, 32-kDa protein that is cleaved from the C terminus of the Gag-Pol polyprotein (Pr160 Gag-Pol ) via viral proteolytic activity.…”

mentioning

confidence: 99%

Sequential Deletion of the Integrase (Gag-Pol) Carboxyl Terminus Reveals Distinct Phenotypic Classes of Defective HIV-1

Mohammed

Topper

Muesing

2011

J Virol

View full text Add to dashboard Cite

A requisite step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is the insertion of the viral genome into that of the host cell, a process catalyzed by the 288-amino-acid (32-kDa) viral integrase (IN). IN recognizes and cleaves the ends of reverse-transcribed viral DNA and directs its insertion into the chromosomal DNA of the target cell. IN function, however, is not limited to integration, as the protein is required for other aspects of viral replication, including assembly, virion maturation, and reverse transcription. Previous studies demonstrated that IN is comprised of three domains: the N-terminal domain (NTD), catalytic core domain (CCD), and C-terminal domain (CTD). Whereas the CCD is mainly responsible for providing the structural framework for catalysis, the roles of the other two domains remain enigmatic. This study aimed to elucidate the primary and subsidiary roles that the CTD has in protein function. To this end, we generated and tested a nested set of IN C-terminal deletion mutants in measurable assays of virologic function. We discovered that removal of up to 15 residues (IN 273) resulted in incremental diminution of enzymatic function and infectivity and that removal of the next three residues resulted in a loss of infectivity. However, replication competency was surprisingly reestablished with one further truncation, corresponding to IN 269 and coinciding with partial restoration of integration activity, but it was lost permanently for all truncations extending N terminal to this position. Our analyses of these replication-competent and -incompetent truncation mutants suggest potential roles for the IN CTD in precursor protein processing, reverse transcription, integration, and IN multimerization.The defining hallmarks of retroviruses are reverse transcription of the viral genomic information as encoded in polyadenylated RNA and the subsequent integration of the copied DNA genome into that of a host cell. The latter is an essential and irreversible event which is mediated by the catalytic activities of the viral integrase protein (IN), the recent target of successful chemotherapeutic intervention against HIV-1 infection (1). HIV-1 IN is a 288-amino-acid, 32-kDa protein that is cleaved from the C terminus of the Gag-Pol polyprotein (Pr160 Gag-Pol ) via viral proteolytic activity. The biochemical mechanisms that lead to retroviral integration, which have been extensively studied in vitro, are defined by two catalytically related and sequentially dependent steps (18) which may be distinguished by their respective sensitivities to current inhibitors of IN function (39). Following the completion of reverse transcription of the viral RNA into its DNA copy, IN removes two nucleotides from the 3Ј end of each strand of the viral DNA. This step, termed 3Ј processing, generates a chemically reactive 3Ј-hydroxyl group (CA OH -3Ј) at the 3Ј ends of the DNA molecule, effectively activating the termini for the subsequent reaction (strand transfer). This enzymatic step is the target of all I...

show abstract

“…Although many compounds have been reported to inhibit IN activity, to date, only the strand transfer inhibitors have been proven to be effective in vivo. While raltegravir (RAL; MK-0518) is currently approved by the FDA for use in both treatment-naïve and treatment-experienced patients, elvitegravir (EVG; GS-9137) is in late stages of clinical development (1,10). Resistance to RAL occurs through three main pathways: Q148H/ K/R, N155H, and less frequently, Y143R/C (3,5).…”

mentioning

confidence: 99%

Cross-Resistance Profile Determination of Two Second-Generation HIV-1 Integrase Inhibitors Using a Panel of Recombinant Viruses Derived from Raltegravir-Treated Clinical Isolates

Wesenbeeck¹,

Rondelez²,

Feyaerts³

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The integrase inhibitor raltegravir (RAL) is currently used for the treatment of both treatment-naïve and treatment-experienced HIV-1-infected patients. Elvitegravir (EVG) is in late phases of clinical development. Since significant cross-resistance between RAL and EVG is observed, there is a need for second-generation integrase inhibitors (INIs) with a higher genetic barrier and limited cross-resistance to RAL/EVG. A panel of HIV-1 integrase recombinants, derived from plasma samples from raltegravir-treated patients (baseline and follow-up samples), were used to study the cross-resistance profile of two second-generation integrase inhibitors, MK-2048 and compound G. Samples with Q148H/R mutations had elevated fold change values with all compounds tested. Although samples with the Y143R/C mutation had reduced susceptibility to RAL, they remained susceptible to MK-2048 and compound G. Samples with the N155H mutation had no reduced susceptibility to compound G. In conclusion, our results allowed ranking of the INIs on the basis of the antiviral activities using recombinant virus stocks from RAL-treated patient viruses. The order according to decreasing susceptibility is compound G, MK-2048, and EVG.

show abstract

Anti-infectives Clinical progress of HIV-1 integrase inhibitors

Cited by 49 publications

References 28 publications

New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

Sequential Deletion of the Integrase (Gag-Pol) Carboxyl Terminus Reveals Distinct Phenotypic Classes of Defective HIV-1

Cross-Resistance Profile Determination of Two Second-Generation HIV-1 Integrase Inhibitors Using a Panel of Recombinant Viruses Derived from Raltegravir-Treated Clinical Isolates

Contact Info

Product

Resources

About