Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants

Ide, Kazuhiko; Aoki, Manabu; Amano, Masayuki; Koh, Yasuhiro; Yedidi, Ravikiran S.; Das, Debananda; Leschenko, Sofiya; Chapsal, Bruno D.; Ghosh, Arun K.; Mitsuya, Hiroaki

doi:10.1128/aac.01540-10

Cited by 27 publications

(30 citation statements)

References 37 publications

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“…The importance of P1/P1= and P2/P2= moieties in targeting multidrug-resistant protease variants has recently become evident (39)(40)(41). Considering the effect of both longer and shorter side chain substitutions at residue 50 in the two double mutants analyzed here (I50V,L), we propose that these moieties in PIs should optimally accommodate S1/S1= and S2/S2= sites in the protease, consistent with the substrate envelope hypothesis (30,42).…”

Section: Discussionmentioning

confidence: 67%

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

Mittal

Bandaranayake

King

et al. 2013

J Virol

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Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, DRV, and ATV susceptibility are influenced by mutations at residue 50 in HIV-1 protease, structural and binding thermodynamics studies were carried out on I50V/L-substituted protease variants in the compensatory mutation A71V background. Reduced affinity to both I50V/A71V and I50L/A71V double mutants is largely due to decreased binding entropy, which is compensated for by enhanced enthalpy for ATV binding to I50V variants and APV binding to I50L variants, leading to hypersusceptibility in these two cases. Analysis of the crystal structures showed that the substitutions at residue 50 affect how APV, DRV, and ATV bind the protease with altered van der Waals interactions and that the selection of I50V versus I50L is greatly influenced by the chemical moieties at the P1 position for APV/DRV and the P2 position for ATV. Thus, the varied inhibitor susceptibilities of I50V/L protease variants are largely a direct consequence of the interdependent changes in protease inhibitor interactions.

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Section: Discussionmentioning

confidence: 67%

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

Mittal

Bandaranayake

King

et al. 2013

J Virol

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“…To our knowledge, the suppression failure of APV-resistant variants has largely been seen in all of the bis-THF-containing PIs thus far published (28,(31)(32)(33). The reduced activity of the bis-THF-containing PIs to block the replication of APV-resistant variants is likely due to the structural similarity between the bis-THF-containing PIs, including GRL-04810, GRL-05010, and DRV.…”

Section: Discussionmentioning

confidence: 99%

GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

Gomez

Amano

Yashchuk

et al. 2013

Antimicrob Agents Chemother

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“…It is particularly noteworthy that we failed to select the A28S amino acid substitution in the present selection experiment of GRL-0739. In our previous studies, strong HIV-1 protease inhibitors, such as TMC-126 and GRL-1398, which contain a paramethoxy group in the P2= site, the A28S amino acid substitution was identified as a resistant variant (23,29). Intriguingly, when HIV-1 NL4-3 was selected with GRL-0519, which contains the same para-methoxy group in the P2= site, the A28S substitution never appeared up to passage 37 (18).…”

Section: Discussionmentioning

confidence: 99%

“…Proviral DNA samples obtained from the lysates of infected cells were subjected to nucleotide sequencing. This drug selection procedure was carried out until the drug concentration reached 5 M, as previously described (28)(29)(30). In the experiments conducted to select drug-resistant variants, the MT-4 cells were also exploited as target cells, since HIV-1 in general replicates at greater levels in MT-4 cells than it does in MT-2 cells, as described above.…”

Section: Cells and Virusesmentioning

confidence: 99%

A Novel Tricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor, GRL-0739, Effectively Inhibits the Replication of Multidrug-Resistant HIV-1 Variants and Has a Desirable Central Nervous System Penetration Property In Vitro

Amano

Tojo

Salcedo-Gómez

et al. 2015

Antimicrob Agents Chemother

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We report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC 50 ], 0.0019 to 0.0036 M), with minimal cytotoxicity (50% cytotoxic concentration [CC 50 ], 21.0 M). GRL-0739 blocked the infectivity and replication of HIV-1 NL4-3 variants selected by concentrations of up to 5 M ritonavir or atazanavir (EC 50 , 0.035 to 0.058 M). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2 ROD variant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous system (CNS) penetration property, as assessed using a novel in vitro blood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS penetration profiles. C ombination antiretroviral therapy (cART) has had a major impact on the AIDS epidemic in industrially advanced nations. Recent analyses have revealed that that mortality rates for HIV-1-infected persons have come close to those of the general population (1-4). Moreover, it is noteworthy that an increase in treatment from previous years, as more people are receiving cART, has brought about a Ͼ30% decline in the number of new infections, particularly in developing areas, including sub-Saharan countries (5). However, no eradication of human immunodeficiency virus type 1 (HIV-1) currently appears to be possible, in part due to the viral reservoirs remaining in the blood and infected tissues. Moreover, we have encountered a number of challenges in bringing about the optimal benefits of the currently available therapeutics for AIDS and HIV-1 infection to individuals receiving cART (6-8). These include (i) drug-related toxicities, (ii) an inability to fully restore normal immunologic functions once individuals have developed full-blown AIDS, (iii) the development of various cancers as a consequence of survival prolongation, (iv) the flaring up of inflammation in individuals receiving cART or immune reconstruction syndrome (IRS), and (v) an increased cost of antiviral...

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Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants

Cited by 27 publications

References 37 publications

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

Structural and Thermodynamic Basis of Amprenavir/Darunavir and Atazanavir Resistance in HIV-1 Protease with Mutations at Residue 50

GRL-04810 and GRL-05010, Difluoride-Containing Nonpeptidic HIV-1 Protease Inhibitors (PIs) That Inhibit the Replication of Multi-PI-Resistant HIV-1 In Vitro and Possess Favorable Lipophilicity That May Allow Blood-Brain Barrier Penetration

A Novel Tricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor, GRL-0739, Effectively Inhibits the Replication of Multidrug-Resistant HIV-1 Variants and Has a Desirable Central Nervous System Penetration Property In Vitro

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