Improved Structure−Activity Relationship Analysis of HIV-1 Protease Inhibitors Using Interaction Kinetic Data

Shuman, Cynthia F.; Vrang, Lotta; Danielson, U. Helena

doi:10.1021/jm0499110

Cited by 41 publications

(20 citation statements)

References 24 publications

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“…The PIs show differential accumulations within lymphoblastoid cell lines (21) and peripheral blood mononuclear cells of virologically suppressed patients in vivo, with NFV and SQV accumulations higher than those of LPV and RTV (24). Thus, the rank order effects of the different PIs on neutrophil functions and apoptosis shown in our study are similar to their reported cell culture efficacies (which represent the concentrations of inhibitor that result in 50% inhibition of HIV type 1 replication [47]) and to their rank order for cellular accumulation (18,24). The significant recovery of neutrophil functions reported after the treatment of HIV patients (35) raises the possibility that the main in vivo effect of the PIs on neutrophils is in reducing the number of functionally defective apoptotic cells (53).…”

Section: Discussionsupporting

confidence: 83%

“…The PIs act by blocking the HIV aspartyl protease, a viral enzyme that cleaves the HIV Gag and Gag-Pol polyprotein backbone, thereby interrupting the viral life cycle. These PIs have been reported to have different affinities, inhibition constants, physiochemical properties, and cell culture efficacies (16,47). The highest cell culture efficacies were detected for SQV and NFV and the lowest for APV.…”

Section: Discussionmentioning

confidence: 99%

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Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Hadad

Lévy

Schlaeffer

et al. 2007

Clin Vaccine Immunol

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Impairment of neutrophil functions and high levels of apoptotic neutrophils have been reported in human immunodeficiency virus (HIV) patients. The aim of the present study was to investigate the direct in vitro effects of the different HIV protease inhibitors (PIs) on neutrophil functions and apoptosis and to explore their mechanisms of action. The effects of nelfinavir (NFV), saquinavir (SQV), lopinavir (LPV), ritonavir (RTV), and amprenavir (APV) in the range of 5 to 100 g/ml on neutrophil function, apoptosis, and -calpain activity were studied. The neutrophil functions studied included superoxide production stimulated by 5 ng/ml phorbol myristate acetate, 5 ؋ 10 ؊7 M N-formyl-methionyl-leucyl-phenylalanine, and 1 mg/ml opsonized zymosan; specific chemotaxis; random migration; and phagocytosis. Apoptosis was determined by DNA fragmentation, fluorescein isothiocyanate-annexin V binding, and nuclear morphology. All three neutrophil functions, as well as apoptosis, were similarly affected by the PIs. SQV and NFV caused marked inhibition and LPV and RTV caused moderate inhibition, while APV had a minor effect. -Calpain activity was not affected by the PIs in neutrophil lysate but was inhibited after its translocation to the membranes after cell stimulation. SQV, which was the most potent inhibitor of neutrophil functions and apoptosis, caused significant inhibition of calpain activity, while APV had no effect. The similar patterns of inhibition of neutrophil functions and apoptosis by the PIs, which coincided with inhibition of calpain activity, suggest the involvement of calpain activity in the regulation of these processes.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Hadad

Lévy

Schlaeffer

et al. 2007

Clin Vaccine Immunol

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“…The calculation of [I]/K i was performed with two different K i values for RTV: the highest K i reported in the literature (55 pM) (17), as the K i values for all PIs were evaluated in the same work, and a mean K i calculated from different works reported in the literature (37.5 pM) (18)(19)(20). Moreover, once the observed [I]/K i values for RTV and for the concomitant PI in each sample were obtained, the ratio between these two values was calculated (RTV 1/concomitant PI 1).…”

Section: Patients and Inclusion Criteriamentioning

confidence: 99%

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Nicolò

Simiele

Calcagno

et al. 2014

Antimicrob Agents Chemother

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Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n ‫؍‬ 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n ‫؍‬ 40), lopinavir-ritonavir 400 and 100 mg twice daily (n ‫؍‬ 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n ‫؍‬ 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, further in vitro and in vivo studies of the RTV antiviral effect are warranted. Infection with HIV is a worldwide health problem, with an estimated burden of 34 million infected patients. With the introduction of highly active antiretroviral therapy (HAART), it has been possible to manage infections and prevent the occurrence of AIDS and HIV-related complications (1, 2). HAART is based on the coadministration of drugs that target several important HIV enzymes or cell coreceptors, including reverse transcriptase, integrase, protease, and CCR5. Currently, protease inhibitor (PI)-based regimens are often adopted for HIV treatment (3, 4). Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction o...

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“…12,13 They act as antibiotics, herbicides, 14 inhibitors of the enzymes renin, EPSP synthase and HIV protease. 15,16 In addition a-amino phosphonates have broad applications due to their antifungal 17 and antibacterial activities. 18 Various synthetic approaches have been reported for the synthesis of a-amino phosphonates, among which the most convenient are the Kabachnik-Fields 19 31 and Mg(ClO 4 ) 32 as well as chiral catalysts 33,34 have been examined.…”

mentioning

confidence: 99%

ZnO Nanoparticles as an Efficient Catalyst for the One-Pot Synthesis of α-Amino Phosphonates

Kassaee¹,

Movahedi²,

Masrouri³

2009

Synlett

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Zinc oxide nanoparticles (ZnO NPs, ca. 22 nm) were used as an effective catalyst in the solvent-free, three-component couplings of aldehydes, aromatic amines and dialkyl phosphites at room temperature to produce various a-amino phosphonates. Compared to known methods, satisfactory results were obtained with high yields through a simple experimental procedure. The catalyst was recycled and reused five times with minor decrease in its catalytic activity.

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Improved Structure−Activity Relationship Analysis of HIV-1 Protease Inhibitors Using Interaction Kinetic Data

Cited by 41 publications

References 24 publications

Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Direct Effect of Human Immunodeficiency Virus Protease Inhibitors on Neutrophil Function and Apoptosis via Calpain Inhibition

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

ZnO Nanoparticles as an Efficient Catalyst for the One-Pot Synthesis of α-Amino Phosphonates

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