Establishment of a new cell line inducibly expressing HIV-1 protease for performing safe and highly sensitive screening of HIV protease inhibitors

Background: Prophylactic treatment regimens to prevent mother-to-child HIV transmission include protease inhibitors Lopinavir and Ritonavir. Lopinavir and Ritonavir have been reported to be able to induce intracellular oxidative stress in diverse cellular models, however scarce informations are available about protease inhibitor effects of in the central nervous system (CNS). In our study we evaluated the impact of protease inhibitors on a cell neuronal model. Methods: We treated a neuroblastoma cell line (SH-SY5Y) with increasing doses of Lopinavir and Ritonavir (0.1-1-10-25-50 µM), used alone or in combination, evaluating the impact of these drugs in terms of mitochondrial activity, with MTT cell proliferation assay; mRNA expression of heme oxygenase (HemeOH) and reactive oxygen species (ROS) levels with 2',7'-dichlorofluorescin diacetate (H2DCFDA) in order to assess oxidative stress; apoptotic cell death with flow cytometry. Results: We observed that Lopinavir and Ritonavir treatment, at 25 and/or 50 µM concentrations, induced mitochondrial damage, increase of heme oxygenase RNA expression levels and ROS generation, followed by apoptosis in SH-SY5Y. Conclusions: Our in vitro model demonstrates a damaging effect of HIV protease inhibitors on the neuroblastoma cell line, thus partially mimicking the impact of these drugs on the CNS of children born to HIV positive mothers undergone to antiretroviral treatment.

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HIV protease inhibitors with picomolar potency against PI-Resistant HIV-1 by extension of the P3 substituent

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/s0960-894x(03)00475-x ◽

2003 ◽

Vol 13 (15) ◽

pp. 2569-2572 ◽

Cited By ~ 11

Author(s):

Joseph L. Duffy ◽

Thomas A. Rano ◽

Nancy J. Kevin ◽

Kevin T. Chapman ◽

William A. Schleif ◽

...

Keyword(s):

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Hiv 1

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Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains

Journal of Medicinal Chemistry ◽

10.1021/jm020537i ◽

2003 ◽

Vol 46 (9) ◽

pp. 1764-1768 ◽

Cited By ~ 29

Author(s):

Hirokazu Tamamura ◽

Yasuhiro Koh ◽

Satoshi Ueda ◽

Yoshikazu Sasaki ◽

Tomonori Yamasaki ◽

...

Keyword(s):

Protease Inhibitors ◽

Multidrug Resistant ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Hiv 1

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.5.1058 ◽

1997 ◽

Vol 41 (5) ◽

pp. 1058-1063 ◽

Cited By ~ 98

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.

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Kinetic and thermodynamic characterisation of HIV-protease inhibitors against E35D↑G↑S mutant in the South African HIV-1 subtype C protease

Journal of Enzyme Inhibition and Medicinal Chemistry ◽

10.1080/14756366.2019.1636234 ◽

2019 ◽

Vol 34 (1) ◽

pp. 1451-1456 ◽

Cited By ~ 1

Author(s):

Sibusiso Maseko ◽

Eden Padayachee ◽

Siyabonga Maphumulo ◽

Thavendran Govender ◽

Yasien Sayed ◽

...

Keyword(s):

Protease Inhibitors ◽

South African ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Subtype C ◽

The South ◽

Hiv 1

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Applications of Click Chemistry in the Development of HIV Protease Inhibitors

International Journal of Medicinal Chemistry ◽

10.1155/2018/2946730 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Mukesh M. Mudgal ◽

Nagaraju Birudukota ◽

Mayur A. Doke

Keyword(s):

Protease Inhibitor ◽

Click Chemistry ◽

Protease Inhibitors ◽

Highly Active Antiretroviral Therapy ◽

Click Reaction ◽

Large Body ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Infected People ◽

Hiv 1

Acquired Immunodeficiency Syndrome (AIDS) has been devastating for millions of people around the world. Inhibition of the human immunodeficiency virus (HIV) protease is among the most important approaches for the therapeutic intervention in HIV infection. Since the discovery of the HIV-1 protease, this enzyme has been considered as a key target for the inhibition of viral replication. A large body of research has been done to develop an effective HIV-1 protease inhibitor. There are to date 10 HIV-1 protease inhibitor drugs approved by the Food and Drug Administration (FDA) that have improved the survival and quality of life of HIV infected people. These drugs are prescribed in combination with the reverse transcriptase inhibitors, which is referred to as highly active antiretroviral therapy (HAART). The HIV-1 protease inhibitors play a vital role in HAART. The applications of click chemistry are dispersing in the field of drug discovery. Recently, click chemistry has captured a lot of attention and has become a powerful tool for the synthesis of medicinal skeletons in the discovery of anti-HIV drugs. Click reaction is a well-known method for making carbon−heteroatom−carbon bonds. Click reactions are popular because they are wide in scope, of high yielding, quick to perform, and easy to purify. In this review, we outlined current approaches towards the development of HIV-1 protease inhibitors employing click chemistry.

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