A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro

Amano, Masayuki; Koh, Yasuhiro; Das, Debananda; Li, Jianfeng; Leschenko, Sofiya; Wang, Yuan Fang; Boross, Péter; Weber, Irene T.; Ghosh, Arun K.; Mitsuya, Hiroaki

doi:10.1128/aac.01413-06

Cited by 65 publications

(104 citation statements)

References 34 publications

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“…Crystal structures of HIV-1 protease with a single mutation (D30N, I50V, V82A, I84V, or L90M) complexed with DRV demonstrate that DRV not only binds to the same catalytic active site as it does for wild-type protease but also maintains hydrogen bond interactions with the backbone atoms of Asp-29 and Asp-30 (40,42). GRL-06579A and GRL-98065 are also potent against multidrug resistant HIV-1 strains, and molecular modeling indicates that for multidrug-resistant clinical isolates, these inhibitors maintain many of the interactions to critical active site residues (26,36). TPV, which is active against HIV-1 carrying multidrug-resistant protease, also maintains critical hydrogen bond interactions with backbone atoms in the catalytic active site of mutant protease (43).…”

Section: Discussionmentioning

confidence: 99%

Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization

Koh

Matsumi

Das

et al. 2007

Journal of Biological Chemistry

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140

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Dimerization of HIV-1 protease subunits is essential for its proteolytic activity, which plays a critical role in HIV-1 replication. Hence, the inhibition of protease dimerization represents a unique target for potential intervention of HIV-1. We developed an intermolecular fluorescence resonance energy transferbased HIV-1-expression assay employing cyan and yellow fluorescent protein-tagged protease monomers. Using this assay, we identified non-peptidyl small molecule inhibitors of protease dimerization. These inhibitors, including darunavir and two experimental protease inhibitors, blocked protease dimerization at concentrations of as low as 0.01 M and blocked HIV-1 replication with IC 50 values of 0.0002-0.48 M. These agents also inhibited the proteolytic activity of mature protease. Other approved anti-HIV-1 agents examined except tipranavir, a CCR5 inhibitor, and soluble CD4 failed to block the dimerization event. Once protease monomers dimerize to become mature protease, mature protease is not dissociated by this dimerization inhibition mechanism, suggesting that these agents block dimerization at the nascent stage of protease maturation. The proteolytic activity of mature protease that managed to undergo dimerization despite the presence of these agents is likely to be inhibited by the same agents acting as conventional protease inhibitors. Such a dual inhibition mechanism should lead to highly potent inhibition of HIV-1.

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Section: Discussionmentioning

confidence: 99%

Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization

Koh

Matsumi

Das

et al. 2007

Journal of Biological Chemistry

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140

182

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“…MT-2 or MT-4 cells (10 5 ) were exposed to each infectious HIV-1 clone (5 ng of p24 Gag protein/ml) for 3 h, washed twice with phosphate-buffered saline, and cultured in 10 ml of complete medium as described previously (1,14). Culture supernatants (50 l) were harvested every other day, and the p24 Gag amounts were determined as described above.…”

Section: Methodsmentioning

confidence: 99%

“…Assays for HIV-1 p24 Gag protein production were performed with MT-4 cells as described previously (1,20,24). In brief, MT-4 cells (10 5 /ml) were exposed to 100 TCID 50 of infectious molecular HIV-1 clones in the presence or absence of various concentrations of drugs and were incubated at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Non-Cleavage Site Gag Mutations in Amprenavir-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance but Delay Development of Resistance to Other Protease Inhibitors

Aoki

Venzon

Koh

et al. 2009

J Virol

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“…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...

show abstract

A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro

Cited by 65 publications

References 34 publications

Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization

Potent Inhibition of HIV-1 Replication by Novel Non-peptidyl Small Molecule Inhibitors of Protease Dimerization

Non-Cleavage Site Gag Mutations in Amprenavir-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance but Delay Development of Resistance to Other Protease Inhibitors

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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