scholarly journals In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine.

1993 ◽  
Vol 37 (4) ◽  
pp. 810-817 ◽  
Author(s):  
S Kageyama ◽  
T Mimoto ◽  
Y Murakawa ◽  
M Nomizu ◽  
H Ford ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Transition State ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Immunodeficiency Virus

scholarly journals Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones

2005 ◽  
Vol 49 (9) ◽  
pp. 3816-3824 ◽  
Author(s):  
S. Weinheimer ◽  
L. Discotto ◽  
J. Friborg ◽  
H. Yang ◽  
R. Colonno
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Treatment Options ◽  
Hiv Infections ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Protease Inhibition ◽  
Immunodeficiency Virus ◽  
Increased Susceptibility

ABSTRACT Substitution of leucine for isoleucine at residue 50 (I50L) of human immunodeficiency virus (HIV) protease is the signature substitution for atazanavir (ATV) resistance. A unique phenotypic profile has been associated with viruses containing the I50L substitution, which produces ATV-specific resistance and increased susceptibility to most other approved HIV protease inhibitors (PIs). The basis for this unique phenotype has not been clearly elucidated. In this report, a direct effect of I50L on the susceptibility to the PI class is described. Cell-based protease assays using wild-type and PI-resistant proteases from laboratory and clinical isolates and in vitro antiviral assays were used to demonstrate a strong concordance between changes in PI susceptibility at the level of protease inhibition and changes in susceptibility observed at the level of virus infection. The results show that the induction of ATV resistance and increased susceptibility to other PIs by the I50L substitution is likely determined at the level of protease inhibition. Moreover, the I50L substitution functions to increase PI susceptibility even in the presence of other primary and secondary PI resistance substitutions. These findings may have implications regarding the optimal sequencing of PI therapies necessary to preserve PI treatment options of patients with ATV-resistant HIV infections.

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

2007 ◽  
Vol 14 (11) ◽  
pp. 1515-1521 ◽  
Author(s):  
Nurit Hadad ◽  
Rachel Levy ◽  
Francisc Schlaeffer ◽  
Klaris Riesenberg
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Neutrophil Function ◽  
Significant Inhibition ◽  
Hiv Protease ◽  
Minor Effect ◽  
Hiv Protease Inhibitors ◽  
Calpain Activity ◽  
Immunodeficiency Virus

ABSTRACT 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 μg/ml on neutrophil function, apoptosis, and μ-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. μ-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.

scholarly journals Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor.

1997 ◽  
Vol 41 (5) ◽  
pp. 1058-1063 ◽  
Author(s):  
S M Poppe ◽  
D E Slade ◽  
K T Chong ◽  
R R Hinshaw ◽  
P J Pagano ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Pharmacokinetic Studies ◽  
Hiv Protease Inhibitors ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

PNU-140690 is a member of a new class of nonpeptidic human immunodeficiency virus (HIV) protease inhibitors (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrones) discovered by structure-based design. PNU-140690 has excellent potency against a variety of HIV type 1 (HIV-1) laboratory strains and clinical isolates, including those resistant to the reverse transcriptase inhibitors zidovudine or delavirdine. When combined with either zidovudine or delavirdine, PNU-140690 contributes to synergistic antiviral activity. PNU-140690 is also highly active against HIV-1 variants resistant to peptidomimetic protease inhibitors, underscoring the structural distinctions between PNU-140690 and substrate analog protease inhibitors. PNU-140690 retains good antiviral activity in vitro in the presence of human plasma proteins, and preclinical pharmacokinetic studies revealed good oral bioavailability. Accordingly, PNU-140690 is a candidate for clinical evaluation.

scholarly journals Model System for High-Throughput Screening of Novel Human Immunodeficiency Virus Protease Inhibitors in Escherichia coli

2004 ◽  
Vol 48 (7) ◽  
pp. 2437-2447 ◽  
Author(s):  
Ting-Jen Cheng ◽  
Ashraf Brik ◽  
Chi-Huey Wong ◽  
Chen-Chen Kan
Keyword(s):  
Escherichia Coli ◽  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
High Throughput ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
E Coli ◽  
Immunodeficiency Virus ◽  
Protease Precursor

ABSTRACT Novel human immunodeficiency virus (HIV) protease inhibitors are urgently needed for combating the drug-resistance problem in the fight against AIDS. To facilitate lead discovery of HIV protease inhibitors, we have developed a safe, convenient, and cost-effective Escherichia coli-based assay system. This E. coli-based system involves coexpression of an engineered β-galactosidase as an HIV protease substrate and the HIV protease precursor comprising the transframe region and the protease domain. Autoprocessing of the HIV protease precursor releases the mature HIV protease. Subsequently, the HIV protease cleaves β-galactosidase, resulting in a loss of the β-galactosidase activity, which can be detected in high-throughput screens. Using Food and Drug Administration-approved HIV protease inhibitors, this E. coli-based system is validated as a surrogate screening system for identifying inhibitors that not only possess inhibitory activity against HIV protease but also have solubility and permeability for in vivo activity. The usefulness of the E. coli-based system was demonstrated with the identification of a novel HIV protease inhibitor from a library of compounds that were prepared by an amide-forming reaction with transition-state analog cores. A novel inhibitor with a sulfonamide core of amprenavir, E2, has shown good correlation with the in vitro enzymatic assay and in vivo E. coli-based system. This system can also be used to generate drug resistance profiles that could be used to suggest therapeutic uses of HIV protease inhibitors to treat the drug-resistant HIV strains. This simple yet efficient E. coli system not only represents a screening platform for high-throughput identification of leads targeting the HIV proteases but also can be adapted to all other classes of proteases.

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