scholarly journals Application of the Lewis Acid–Lewis Base Bifunctional Asymmetric Catalysts to Pharmaceutical Syntheses: Stereoselective Chiral Building Block Syntheses of Human Immunodeficiency Virus (HIV) Protease Inhibitor and β3-Adenergic Receptor Agonist

2003 ◽  
Vol 51 (6) ◽  
pp. 702-709 ◽  
Author(s):  
Hiroyuki Nogami ◽  
Motomu Kanai ◽  
Masakatsu Shibasaki
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Lewis Acid ◽  
Building Block ◽  
Receptor Agonist ◽  
Lewis Base ◽  
Hiv Protease ◽  
Asymmetric Catalysts ◽  
Immunodeficiency Virus ◽  
Chiral Building Block

scholarly journals Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication.

1996 ◽  
Vol 40 (6) ◽  
pp. 1346-1351 ◽  
Author(s):  
C A Deminie ◽  
C M Bechtold ◽  
D Stock ◽  
M Alam ◽  
F Djang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combination Therapy ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Nucleoside Analogs ◽  
Drug Combinations ◽  
Hiv Protease ◽  
Human Immunodeficiency Virus Replication ◽  
Immunodeficiency Virus

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.

scholarly journals ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease

1998 ◽  
Vol 42 (12) ◽  
pp. 3218-3224 ◽  
Author(s):  
Hing L. Sham ◽  
Dale J. Kempf ◽  
Akhteruzammen Molla ◽  
Kennan C. Marsh ◽  
Gondi N. Kumar ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Response To Therapy ◽  
Hiv Protease ◽  
Healthy Human ◽  
Human Volunteers ◽  
Immunodeficiency Virus ◽  
Potent Protease Inhibitor

ABSTRACT The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

scholarly journals In vitro anti-human immunodeficiency virus (HIV) activity of XM323, a novel HIV protease inhibitor.

1993 ◽  
Vol 37 (12) ◽  
pp. 2606-2611 ◽  
Author(s):  
M J Otto ◽  
C D Reid ◽  
S Garber ◽  
P Y Lam ◽  
H Scarnati ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor ◽  
Immunodeficiency Virus

An analysis of the delay-dependent HIV-1 protease inhibitor model

2018 ◽  
Vol 11 (03) ◽  
pp. 1850031
Author(s):  
M. Divya ◽  
M. Pitchaimani
Keyword(s):  
Human Immunodeficiency Virus ◽  
Sensitivity Analysis ◽  
Stability Analysis ◽  
Protease Inhibitor ◽  
Numerical Simulations ◽  
Humoral Immunity ◽  
Hiv Protease ◽  
Immunodeficiency Virus ◽  
Delay Dependent ◽  
Hiv 1

In this paper, we have studied about the sensitivity analysis of the human immunodeficiency virus (HIV) protease inhibitor (PI) model and estimated the length of the delay. We have fabricated an HIV PI model accompanied with humoral immunity. Stability analysis of the constructed model about its steady states has been deliberated. We have evaluated some numerical simulations for PI model with humoral immunity by using the existing patient data.

scholarly journals The human immunodeficiency virus (HIV) protease inhibitor indinavir directly affects the opportunistic fungal pathogenCryptococcus neoformans

2004 ◽  
Vol 42 (2) ◽  
pp. 187-195 ◽  
Author(s):  
Elisabetta Blasi ◽  
Bruna Colombari ◽  
Carlotta Francesca Orsi ◽  
Marcello Pinti ◽  
Leonarda Troiano ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor ◽  
Immunodeficiency Virus

scholarly journals Penetration of Atazanavir in Seminal Plasma of Men Infected with Human Immunodeficiency Virus Type 1

2006 ◽  
Vol 51 (1) ◽  
pp. 335-337 ◽  
Author(s):  
E. van Leeuwen ◽  
R. ter Heine ◽  
F. van der Veen ◽  
S. Repping ◽  
J. H. Beijnen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Blood Plasma ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Seminal Plasma ◽  
Exploratory Study ◽  
Hiv Protease ◽  
Immunodeficiency Virus

ABSTRACT In this exploratory study, the human immunodeficiency virus (HIV) protease inhibitor atazanavir was detected in seminal plasma in 15 out of 15 HIV-infected men taking an atazanavir-containing regimen. However, this penetration was limited and variable, and the median seminal/blood plasma ratio was only 0.1.

scholarly journals A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro

2007 ◽  
Vol 51 (6) ◽  
pp. 2143-2155 ◽  
Author(s):  
Masayuki Amano ◽  
Yasuhiro Koh ◽  
Debananda Das ◽  
Jianfeng Li ◽  
Sofiya Leschenko ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Close Contact ◽  
Wide Spectrum ◽  
Antiviral Agents ◽  
Cyclic Ether ◽  
Hiv Protease ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to 0.0005 μM) with minimal cytotoxicity (50% cytotoxicity, 35.7 μM in CD4+ MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1NL4-3 variants exposed to and selected by up to a 5 μM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 μM concentration of lopinavir or atazanavir (EC50, 0.0015 to 0.0075 μM), although it was less active against HIV-1NL4-3 selected by amprenavir (EC50, 0.032 μM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.

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