Prevalence, Mutation Patterns, and Effects on Protease Inhibitor Susceptibility of the L76V Mutation in HIV-1 Protease

Young, Thomas P.; Parkin, Neil; Stawiski, Eric; Pilot‐Matias, Tami; Trinh, Roger; Kempf, Dale J.; Norton, Michael

doi:10.1128/aac.00906-10

Cited by 32 publications

(52 citation statements)

References 26 publications

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“…An L33V substitution was also observed in 4 of the 26 clones by passage 37. Reportedly, APV-resistant HIV-1 variants contain V32I, I50V, I54L/M, L76V, I84V, and L90M substitutions (30,31), and such substitutions were also identified in the present study (data not shown). However, no such APV resistance-associated amino acid substitutions emerged during the GRL-0519 selection (Fig.…”

Section: In Vitro Selection Of Hiv-1 Variants Resistant To Grl-0519supporting

confidence: 51%

GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro

Amano

Tojo

Salcedo-Gómez

et al. 2013

Antimicrob Agents Chemother

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dWe report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing tris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC 50 ], 0.0005 to 0.0007 M) with minimal cytotoxicity (50% cytotoxic concentration [CC 50 ], 44.6 M). GRL-0519 blocked the infectivity and replication of HIV-1 NL4-3 variants selected by up to a 5 M concentration of ritonavir, lopinavir, or atazanavir (EC 50 , 0.0028 to 0.0033 M). GRL-0519 was also potent against multi-PIresistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2 ROD . The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that the tris-THF moiety, compared to the bis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that the tris-THF moiety and paramethoxy group effectively fill the S2 and S2= binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PIresistant variants and that the tris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics.

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Section: In Vitro Selection Of Hiv-1 Variants Resistant To Grl-0519supporting

confidence: 51%

GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro

Amano

Tojo

Salcedo-Gómez

et al. 2013

Antimicrob Agents Chemother

View full text Add to dashboard Cite

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“…Reportedly, APV-resistant HIV-1 variants contain the V32I, I50V, I54L/M, L76V, I84V, and L90M substitutions (36,37), and such substitutions were also identified in the present study (data not shown). However, except for I84V, none of these APV resistance-associated amino acid substitutions emerged during the GRL-0739 selection ( Fig.…”

Section: Discussionsupporting

confidence: 48%

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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“…We identified mutations at 25 positions among the 57 HIV-1-infected patients who developed resistance to PI/r, with a predominance of the M46I and L76V/E mutations, each representing 24% of the total. These common mutations have been associated with a decrease in susceptibility to lopinavir (LPV)/ritonavir and indinavir (IDV)/ritonavir but an increase in susceptibility to atazanavir and saquinavir (40).…”

Section: Hiv-1 Drug Resistance In Public Health Systemmentioning

confidence: 99%

HIV-1 Genetic Diversity and Drug Resistance among Senegalese Patients in the Public Health System

et al. 2013

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In this study, we investigated the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations and genetic variability among Senegalese patients undergoing highly active antiretroviral therapy (ART) in the public health system. We conducted a cross-sectional study of 72 patients with suspected therapeutic failure. HIV-1 genotyping was performed with Viroseq HIV-1 Genotyping System v2.0 or the procedure developed by the ANRS AC11 resistance study group, and a phylogenetic analysis was performed. The median follow-up visit was at 40 (range, 12 to 123) months, and the median viral load was 4.67 (range, 3.13 to 6.94) log 10 copies/ml. The first-line therapeutic regimen was nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz (EFV) or NRTIs plus nevirapine (NVP) (54/72 patients; 75%), and the second-line therapy was NRTIs plus a protease inhibitor (PI/r) (18/72; 25%). Fifty-five patients (55/72; 76.39%) had at least one drug resistance mutation. The drug resistance rates were 72.22 and 88.89% for the first-line and second-line ARTs, respectively. In NRTI mutations, thymidine analog mutations (TAMs) were found in 50.79% and the M184V mutation was found in 34.92% of the samples. For non-NRTI resistance, we noted a predominance of the K103N mutation (46.27%). For PI/r, several cases of mutations were found with a predominance of M46I and L76V/F at 24% each. The phylogenetic analysis revealed CRF02_AG as the predominant circulating recombinant form (43/72; 59.72%). We found a high prevalence of resistance mutations and a high rate of TAMs among Senegalese patients in the public health system. These findings emphasize the need to improve virological monitoring in resource-limited settings.

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Prevalence, Mutation Patterns, and Effects on Protease Inhibitor Susceptibility of the L76V Mutation in HIV-1 Protease

Cited by 32 publications

References 26 publications

GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro

GRL-0519, a Novel Oxatricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor (PI), Potently Suppresses Replication of a Wide Spectrum of Multi-PI-Resistant HIV-1 Variants In Vitro

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

HIV-1 Genetic Diversity and Drug Resistance among Senegalese Patients in the Public Health System

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