scholarly journals Lack of Antiviral Activity of Darunavir against SARS-CoV-2

2020 ◽  
Author(s):  
Sandra De Meyer ◽  
Denisa Bojkova ◽  
Jindrich Cinatl ◽  
Ellen Van Damme ◽  
Christophe Buyck ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Positive Control ◽  
Hiv Protease ◽  
Fixed Dose ◽  
Hiv Protease Inhibitors ◽  
Cyp3a4 Inhibitor ◽  
Immunodeficiency Virus ◽  
Dose Combination ◽  
Therapeutic Alternatives

AbstractGiven the high need and the absence of specific antivirals for treatment of COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Prezcobix/Rezolsta is a fixed-dose combination of 800 mg of the HIV protease inhibitor darunavir (DRV) and 150 mg cobicistat, a CYP3A4 inhibitor, which is indicated in combination with other antiretroviral agents for the treatment of HIV infection. There are currently no definitive data on the safety and efficacy of DRV/cobicistat for treatment of COVID-19. The in vitro antiviral activity of darunavir against a clinical isolate from a patient infected with SARS-CoV-2 was assessed. DRV showed no activity against SARS-CoV-2 at clinically relevant concentrations (EC50 >100 μM). Remdesivir, used as a positive control, showed potent antiviral activity (EC50 = 0.38 μM). Overall, the data do not support the use of DRV for treatment of COVID-19.

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 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 Molecular and Enzymatic Characterization of the Porcine Endogenous Retrovirus Protease

2002 ◽  
Vol 76 (15) ◽  
pp. 7913-7917 ◽  
Author(s):  
Jürgen H. Blusch ◽  
Sigrid Seelmeir ◽  
Klaus von der Helm
Keyword(s):  
High Specificity ◽  
Endogenous Retrovirus ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Amino Acid Residues ◽  
Porcine Endogenous Retrovirus ◽  
Immunodeficiency Virus ◽  
Retroviral Proteases

ABSTRACT The protease of the porcine endogenous retrovirus (PERV) subtypes A/B and C was recombinantly expressed in Escherichia coli as proteolytically active enzyme and characterized. The PERV Gag precursor was also recombinantly produced and used as the substrate in an in vitro enzyme assay in parallel with synthetic nonapeptide substrates designed according to cleavage site sequences identified in the PERV Gag precursor. The proteases of all PERV subtypes consist of 127 amino acid residues with an M r of 14,000 as revealed by determining the protease N and C termini. The PERV proteases have a high specificity for PERV substrates and do not cleave human immunodeficiency virus (HIV)-specific substrates, nor are they inhibited by specific HIV protease inhibitors. Among the known retroviral proteases, the PERV proteases resemble most closely the protease of the murine leukemia retrovirus.

scholarly journals Development, Characterization and In Vivo Pharmacokinetic Assessment of Rectal Suppositories Containing Combination Antiretroviral Drugs for HIV Prevention

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1110
Author(s):  
Kunal Jhunjhunwala ◽  
Charles W. Dobard ◽  
Sunita Sharma ◽  
Natalia Makarova ◽  
Angela Holder ◽  
...  
Keyword(s):  
Hiv Prevention ◽  
Antiretroviral Drugs ◽  
Water Soluble ◽  
Fixed Dose ◽  
Receptive Anal Intercourse ◽  
On Demand ◽  
Dose Combination ◽  
Rectal Suppositories

Receptive anal intercourse (RAI) contributes significantly to HIV acquisition underscoring the need to develop HIV prevention options for populations engaging in RAI practices. We explored the feasibility of formulating rectal suppositories with potent antiviral drugs for on-demand use. A fixed-dose combination of tenofovir (TFV) and elvitegravir (EVG) (40 mg each) was co-formulated in six different suppository bases (three fat- and three water-soluble). Fat-soluble witepsol H15 and water-soluble polyethylene glycol (PEG) based suppositories demonstrated favorable in vitro release and were advanced to assess in vivo pharmacokinetics following rectal administration in macaques. In vivo drug release profiles were similar for both suppository bases. Median concentrations of TFV and EVG detected in rectal fluids at 2 h were 1- and 2-logs higher than the in vitro IC50, respectively; TFV-diphosphate levels in rectal tissues met or exceeded those associated with high efficacy against rectal simian HIV (SHIV) exposure in macaques. Leveraging on these findings, a PEG-based suppository with a lower dose combination of tenofovir alafenamide (TAF) and EVG (8 mg each) was developed and found to achieve similar rectal drug exposures in macaques. This study establishes the utility of rectal suppositories as a promising on-demand strategy for HIV PrEP and supports their clinical development.

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