Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor

Markowitz, Martin; Mo, Hongmei; Kempf, Dale J.; Norbeck, Daniel W.; Bhat, Talapady N.; Erickson, John W.; Ho, David D.

doi:10.1128/jvi.69.2.701-706.1995

Cited by 212 publications

(115 citation statements)

References 33 publications

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“…These mutations were not described previously with the use of unboosted APV in naive or PI experienced patients [Tisdale et al, 2000;Maguire et al, 2002;Ait-Khaled et al, 2003]. These mutations could be selected either by APV itself or by ritonavir low dose, as they were previously described among patients failing to ritonavir monotherapy [Markowitz et al, 1995;Molla et al, 1996]. Previous studies have shown that substitutions at nine different codons can be selected by ritonavir, such as V82A/F/T/S, I84V, and L90M.…”

Section: Discussionmentioning

confidence: 67%

Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients

Marcelin

Affolabi

Lamotte

et al. 2004

Journal of Medical Virology

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Amprenavir (APV) is an HIV protease inhibitor (PI) used for the treatment of either naive or PI-experienced HIV-infected patients. Several genotypic resistance pathways in protease gene have been described to be associated to unboosted APV failure (I50V, V32I + I47V, I54L/M, or less commonly I84V, which may be accompanied by one ore more accessory mutations such as L10F, L33F, M46I/L). The aims of this study were to investigate the efficacy up to week 24 of an APV plus ritonavir containing regimen in PI experienced patients and to determine the genotypic resistance profiles emerging in patients failing to this therapy. Forty-nine, PI experienced but APV naïve patients were treated with APV (600 mg bid) plus ritonavir (100 mg bid). By intent-to-treat analysis, the median decrease in viral load (VL) was -1.32 log10 (min +0.6; max -2.8) and -1.46 log10 (min +0.5; max -2.8) 12 and 24 weeks after initiating APV plus ritonavir regimen, respectively. Twelve patients harboured a VL >200 copies/ml at week 24. Among these patients, the selection of mutations previously described with the use of APV as first PI (V32I, L33F, M46I/L, I50V, 54M/L, and I84V) was observed. However, in some cases, mutations classically described after the use of other PIs (V82F and L90M) were selected but always with APV-specific mutations. There was no relation between the resistance pathways selected with either APV or ritonavir plasma minimal concentration, but higher APV plasma minimal concentration were associated with a lower rate of resistance mutations selection.

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Section: Discussionmentioning

confidence: 67%

Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients

Marcelin

Affolabi

Lamotte

et al. 2004

Journal of Medical Virology

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“…The loss of sensitivity to protease inhibitors usually occurs because the resistant viral strains encode for protease molecules containing specific amino acid mutations that lower the affinity for the inhibitors, yet maintain sufficient affinity for the substrate; that is, the impact of these mutations is more pronounced on inhibitor binding than on substrate binding. Previously, we reported the thermodynamic analysis of the binding of four protease inhibitors in clinical use (Indinavir, Saquinavir, Nelfinavir, and Ritonavir;Todd et al 2000) and a second-generation inhibitor (KNI-764;Velazquez-Campoy et al 2001a) to the wild-type and the drug-resistant double mutant V82F/I84V, known to affect all clinical inhibitors including Amprenavir (Markowitz et al 1995;Ala et al 1998;Klabe et al 1998). The V82F/I84V mutation is located at the edges of the active site (Fig.…”

mentioning

confidence: 99%

Overcoming drug resistance in HIV‐1 chemotherapy: The binding thermodynamics of Amprenavir and TMC‐126 to wild‐type and drug‐resistant mutants of the HIV‐1 protease

et al. 2002

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Amprenavir is one of six protease inhibitors presently approved for clinical use in the therapeutic treatment of AIDS. Biochemical and clinical studies have shown that, unlike other inhibitors, Amprenavir is severely affected by the protease mutation I50V, located in the flap region of the enzyme. TMC-126 is a secondgeneration inhibitor, chemically related to Amprenavir, with a reported extremely low susceptibility to existing resistant mutations including I50V. In this paper, we have studied the thermodynamic and molecular origin of the response of these two inhibitors to the I50V mutation and the double active-site mutation V82F/I84V that affects all existing clinical inhibitors. Amprenavir binds to the wild-type HIV-1 protease with high affinity (5.0 × 10 9 M −1 or 200 pM) in a process equally favored by enthalpic and entropic contributions. The mutations I50V and V82F/I84V lower the binding affinity of Amprenavir by a factor of 147 and 104, respectively. TMC-126, on the other hand, binds to the wild-type protease with extremely high binding affinity (2.6 × 10 11 M −1 or 3.9 pM) in a process in which enthalpic contributions overpower entropic contributions by almost a factor of 4. The mutations I50V and V82F/I84V lower the binding affinity of TMC-126 by only a factor of 16 and 11, respectively, indicating that the binding affinity of TMC-126 to the drug-resistant mutants is still higher than the affinity of Amprenavir to the wild-type protease. Analysis of the data for TMC-126 and KNI-764, another second-generation inhibitor, indicates that their low susceptibility to mutations is caused by their ability to compensate for the loss of interactions with the mutated target by a more favorable entropy of binding.Keywords: HIV-1 protease; drug resistance; HIV-1 protease inhibitors; isothermal titration calorimetry; Amprenavir; TMC-126 A major limiting factor in the treatment of the HIV-1 infection is the emergence of viral strains that show resistance to protease inhibitors (Ho et al. 1994;Kaplan et al. 1994;Condra et al. 1995;Roberts 1995;Hong et al. 1996;Tisdale 1996;Ala et al. 1997;Jadhav et al. 1997;Todd et al. 2000). It has been estimated that one out of every seven new infections in America is caused by viral strains resistant to at least one type of inhibitor. The loss of sensitivity to protease inhibitors usually occurs because the resistant viral strains encode for protease molecules containing specific amino acid mutations that lower the affinity for the inhibitors, yet maintain sufficient affinity for the substrate; that is, the impact of these mutations is more pronounced on inhibitor binding than on substrate binding.

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“…The fortuitous strong inhibition of the P450-3A4 metabolism pathway resulted in a strikingly long half-life for RTV. However, another limitation of RTV monotherapy was its low genetic barrier to resistance, with mutations at codons 82 or 84 substantially reducing viral susceptibility (Markowitz et al 1995a). The selection of protease variants with reduced affinity for RTV is consistent with the hydrophobic interaction between RTV and the isopropyl side chain of Val 82 as observed by X-ray crystallography.…”

Section: Clinical Use Of Hiv-1 Protease Inhibitors and Evolution Of Rmentioning

confidence: 99%

Viral Protease Inhibitors

Anderson

Schiffer

Lee

et al. 2009

Antiviral Strategies

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This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HIV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HIV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is limited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufficiently ubiquitous that treating an acute infection would be beneficial even if the infection was ultimately self-limiting. Protease inhibitor development is most advanced for hepatitis C virus (HCV), and we also provide a review of HCV NS3/4A serine protease inhibitor development, including combination therapy and resistance. Finally, we discuss other viral proteases as potential drug targets, including those from Dengue virus, cytomegalovirus, rhinovirus, and coronavirus.

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Selection and analysis of human immunodeficiency virus type 1 variants with increased resistance to ABT-538, a novel protease inhibitor

Cited by 212 publications

References 33 publications

Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients

Resistance profiles observed in virological failures after 24 weeks of amprenavir/ritonavir containing regimen in protease inhibitor experienced patients

Overcoming drug resistance in HIV‐1 chemotherapy: The binding thermodynamics of Amprenavir and TMC‐126 to wild‐type and drug‐resistant mutants of the HIV‐1 protease

Viral Protease Inhibitors

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