MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir

Métifiot, Mathieu; Johnson, Barry C.; Smith, Steven J.; Zhao, Xue Zhi; Marchand, Christophe; Burke, Terrence R.; Hughes, Stephen H.; Pommier, ﻿Yves

doi:10.1128/aac.05288-11

Cited by 34 publications

(32 citation statements)

References 20 publications

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“…It should be noted that the overall ⌬E binding of RAL is 0.5 kcal/mol lower than DTG in our calculations. The in vitro 50% inhibitory concentrations (IC 50 s) of RAL and DTG were reported to be 26 nM and 33 nM, respectively (30,46). The slightly lower IC 50 for RAL against WT HIV-1 IN than for DTG agrees with our calculation that the binding energy of RAL is slightly lower than that of DTG.…”

Section: Verificationsupporting

confidence: 79%

“…The in vitro activity of DTG against this mutant has not been reported, but this The interaction potentials of RAL and EVG were substantially higher against the G140S/Q148H mutant, and this correlated with a corresponding loss of potency. IC 50 s were determined as described previously (46). …”

Section: Verificationmentioning

confidence: 99%

“…Mutations at position Q148 are often accompanied by a secondary mutation at position G140. The G140S/Q148H double mutant forms a hydrogen bond network across the flexible loop of IN (31); these mutations reduce the susceptibility of IN to both RAL and EVG (47), while susceptibility to MK-0536 and DTG is only modestly affected (30,46). N155 is positioned such that it makes Van der Waals contacts with both D64 and E152 of the catalytic triad and likely reduces susceptibility to RAL and EVG by altering the binding geometry around the Mg 2ϩ ions (Fig.…”

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confidence: 99%

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Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

Johnson

Métifiot

Pommier

et al. 2012

Antimicrob Agents Chemother

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The design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the viral DNA to inhibitor binding. Using the structure of PFV IN as the starting point, we generated a model of the corresponding HIV-1 complex and developed a molecular dynamics (MD)-based approach that correlates with the in vitro activities of novel compounds. Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for their in vitro activity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data. Three additional compounds were docked into the IN-DNA complex model and subjected to MD simulations. All three gave interaction potentials within 1 standard deviation of values estimated from the training set, and the most active compound was identified. Additional MD analysis of the raltegravir-and dolutegravir-bound complexes gave internal and interaction energy values that closely match the experimental binding energy of a compound related to raltegravir that has similar activity. These approaches can be used to gain a deeper understanding of the interactions of the inhibitors with the HIV-1 intasome and to identify promising scaffolds for novel integrase inhibitors, in particular, compounds that retain activity against a range of drug-resistant mutants, making it possible to streamline synthesis and testing. . This leaves a conserved CA sequence with a free hydroxyl on each of the 3= ends of the viral DNA and a 2-nucleotide overhang on each of the 5= ends. In the second reaction, IN uses the newly created 3= hydroxyl to attack the phosphodiester backbone of the host genome (strand transfer [ST]). Depending on the retrovirus, the two viral ends are inserted 4 to 6 bases apart, creating a small duplication in the target DNA flanking the provirus (5 nucleotides in the case of HIV-1 and 4 for prototype foamy virus [PFV]) (50). Cellular enzymes repair the gaps, leaving the double-stranded proviral DNA stably integrated into the genome of the infected cell.Integrases consist of three functionally distinct domains that have been characterized by biochemical and mutational analyses. The N-terminal domain (NTD; residues 1 to 50) contains a zincbinding HHCC motif and contributes to multimer formation (7,8). The C-terminal domain (CTD; identified as residues 212 to 288 in deletion studies) nonspecifically binds DNA (18,20,34,42). The catalytic core domain (CCD; residues 50 to 212) contains the catalytic triad DD35E motif that is well conserved among the retroviral integrase superfamily (7,11,19,32). This active site coordinates two metal ions and binds one viral DNA end. Although IN complexes exist in solution in different multimeric states, recent crystallographic data confirmed that the functi...

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Section: Verificationsupporting

confidence: 79%

Section: Verificationmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

Johnson

Métifiot

Pommier

et al. 2012

Antimicrob Agents Chemother

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“…Although our previously reported method was originally based on the PDB:3L2T crystallographic structure of PFV-IN intasome in complex with raltegravir, 14 we decided to adapt it to the more recent 3S3M X-ray structure of the PFV intasome bound to dolutegravir (see Supporting Information). 16 Whereas the invariant 3′-deoxyadenosine is flipped out of the active site in the case of elvitegravir and MK-0536, a raltegravir-derived INSTI with improved resistance profile, 17 it seems to participate in additional π-stacking interactions with the core of dolutegravir in the 3S3M structure. In a similar manner, the extended planar aromatic nature of our N-hydroxyisoquinoline-1,3-dione core bearing the metal chelating pharmacophore infers a great propensity to interact with this 3′-deoxyadenosine via π-stacking contacts.…”

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confidence: 99%

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Billamboz

Suchaud

Bailly

et al. 2013

ACS Med. Chem. Lett.

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A series of 2-hydroxy-1,3-dioxoisoquinoline-4-carboxamides featuring an N-hydroxyimide chelating functionality was evaluated for their inhibitory properties against human immunodeficiency virus type 1 integrase (HIV-1 IN). Several derivatives displayed low nanomolar IC 50 values comparable to that of the clinically used raltegravir. A marked effect of one compound on both primary IN-catalyzed reactions, strand transfer (ST), and 3′ processing (3′-P), emphasizes a novel IN inhibition mechanism establishing it as a potential new generation IN inhibitor. Substitution of the 2-hydroxyisoquinoline-1,3-dione scaffold at position 4 by carboxamido chains was beneficial for antiviral activity since reproducible low micromolar anti-HIV activities were obtained for the first time within this scaffold.

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“…highest concentration evaluated in this study (24 (20)(21)(22). The influence of PK variability on the efficacy of the raltegravir dosing interval.…”

Section: Figmentioning

confidence: 99%

Pharmacokinetic Determinants of Virological Response to Raltegravir in the In Vitro Pharmacodynamic Hollow-Fiber Infection Model System

Brown

Adams

Baluya

et al. 2015

Antimicrob Agents Chemother

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Daily administration (q24h) of raltegravir has been shown to be as efficacious as twice-daily administration (q12h) in the hollow-fiber infection model (HFIM) system. However, q24h regimens were not noninferior to q12h dosing in a clinical trial. We hypothesized that between-patient variability in raltegravir pharmacokinetics (PK) was responsible for the discordance in conclusions between the in vitro and in vivo studies. Hollow-fiber cartridges were inoculated with HIV-infected H9 cells and uninfected CEM-SS cells. Four cartridges received the total daily exposure (800 mg) q24h and four received half the daily exposure (400 mg) q12h. PK profiles with half-lives of 8, 4, 3, and 2 h were simulated for each dosing interval. Cell-to-cell viral spread was assessed by flow cytometry. Viral inhibition was similar between q24h and q12h dosing at the 8-and 4-h half-lives. The q24h dosing was not as efficacious as the q12h dosing when faster half-lives were simulated; a lack of viral suppression was observed at days 3 and 4 for the 2-and 3-h half-lives, respectively. The discrepancy in conclusions between the in vitro HFIM system studies and clinical trials is likely due to the large interindividual variation in raltegravir PK. Raltegravir is an HIV-1 integrase inhibitor that is used in combination with other antiretroviral agents to treat patients with HIV-1 infections. Raltegravir-based combination chemotherapeutic regimens have been shown to be well tolerated and highly efficacious in both treatment-naive (1-5) and treatment-experienced (6-8) patient populations compared to other combination regimens. Raltegravir is currently administered as a 400-mg twicedaily (BID) dose. A once-daily (QD) raltegravir regimen would be preferable in a clinical setting, since the convenience of a QD regimen would likely improve patient adherence.Previous work done by others has shown that, once bound, raltegravir remains in the active site of the HIV-1 integrase protein for a long time, demonstrating dissociative half-lives ranging from 7.3 to 8.8 h (9, 10). The long occupancy time of raltegravir in the binding pocket of viral integrase suggests that once-daily dosing (800 mg QD) may be as efficacious as the current regimen of 400 mg BID. Moreover, data generated using an in vitro pharmacodynamic (PD) hollow-fiber infection model (HFIM) system supported this speculation (11). Given the strong in vitro support of once-daily dosing, Merck conducted a phase 3 noninferiority trial to compare the efficacy of raltegravir administered as 800 mg QD to the standard dosage regimen of 400 mg BID. The findings of this clinical study showed that both regimens yielded high response rates in vivo, but once-daily dosing did not achieve the Ϫ10% noninferiority margin and was deemed not noninferior to the twice-daily regimen (12). Our objectives for this study were to explain the discordance in conclusions between the in vitro experiments and human clinical studies for raltegravir and to identify the pharmacokinetic-pharmacodynamic (PK-PD) determinants ...

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MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir

Cited by 34 publications

References 20 publications

Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

4-Substituted 2-Hydroxyisoquinoline-1,3(2H,4H)-diones as a Novel Class of HIV-1 Integrase Inhibitors

Pharmacokinetic Determinants of Virological Response to Raltegravir in the In Vitro Pharmacodynamic Hollow-Fiber Infection Model System

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