scholarly journals The HIV protease inhibitor, ritonavir, corrects diverse brain phenotypes across development in mouse model of DYT-TOR1A dystonia

2021 ◽  
Vol 13 (607) ◽  
pp. eabd3904
Author(s):  
Zachary F. Caffall ◽  
Bradley J. Wilkes ◽  
Ricardo Hernández-Martinez ◽  
Joseph E. Rittiner ◽  
Jennifer T. Fox ◽  
...  
Keyword(s):  
Mouse Model ◽  
Protease Inhibitor ◽  
Diffusion Tensor ◽  
Hiv Protease ◽  
Drug Candidate ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Protein Variant ◽  
Oral Medications ◽  
Disease Modifying

Dystonias are a group of chronic movement–disabling disorders for which highly effective oral medications or disease-modifying therapies are lacking. The most effective treatments require invasive procedures such as deep brain stimulation. In this study, we used a high-throughput assay based on a monogenic form of dystonia, DYT1 (DYT-TOR1A), to screen a library of compounds approved for use in humans, the NCATS Pharmaceutical Collection (NPC; 2816 compounds), and identify drugs able to correct mislocalization of the disease-causing protein variant, ∆E302/3 hTorsinA. The HIV protease inhibitor, ritonavir, was among 18 compounds found to normalize hTorsinA mislocalization. Using a DYT1 knock-in mouse model to test efficacy on brain pathologies, we found that ritonavir restored multiple brain abnormalities across development. Ritonavir acutely corrected striatal cholinergic interneuron physiology in the mature brain and yielded sustained correction of diffusion tensor magnetic resonance imaging signals when delivered during a discrete early developmental window. Mechanistically, we found that, across the family of HIV protease inhibitors, efficacy correlated with integrated stress response activation. These preclinical results identify ritonavir as a drug candidate for dystonia with disease-modifying potential.

Design and synthesis of HIV protease inhibitors. Variations of the carboxyterminus of the HIV protease inhibitor L-682,679

1991 ◽  
Vol 34 (9) ◽  
pp. 2852-2857 ◽  
Author(s):  
S. Jane DeSolms ◽  
Elizabeth A. Giuliani ◽  
James P. Guare ◽  
Joseph P. Vacca ◽  
William M. Sanders ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Design And Synthesis

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor

1999 ◽  
Vol 7 (12) ◽  
pp. 2775-2800 ◽  
Author(s):  
J.V.N. Vara Prasad ◽  
Frederick E. Boyer ◽  
John M. Domagala ◽  
Edmund L. Ellsworth ◽  
Christopher Gajda ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Antiviral Activities

scholarly journals Comparing the Greenness and Sustainability of Three Routes to an HIV Protease Inhibitor Intermediate

2021 ◽  
Author(s):  
Roger Arthur Sheldon ◽  
Moira Leanne Bode ◽  
Stephanie Gina Akakios
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hiv Protease Inhibitor

The greenness and sustainability of three different routes for the synthesis of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol (bis-furan alcohol), an advanced intermediate for a group of HIV protease inhibitors, including the FDA...

scholarly journals Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C

2006 ◽  
Vol 291 (6) ◽  
pp. C1271-C1278 ◽  
Author(s):  
Emily L. Bradshaw ◽  
Xiang-An Li ◽  
Theresa Guerin ◽  
William V. Everson ◽  
Melinda E. Wilson ◽  
...  
Keyword(s):  
Side Effects ◽  
Protein Kinase ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Reverse Transcriptase Inhibitors ◽  
Hiv Protease Inhibitor ◽  
Cholesterol Accumulation

HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that α-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using α-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of α-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, α-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Cα (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.

Altered Myocellular and Abdominal Fat Partitioning Predict Disturbance in Insulin Action in HIV Protease Inhibitor-Related Lipodystrophy

Diabetes ◽  
2002 ◽  
Vol 51 (11) ◽  
pp. 3163-3169 ◽  
Author(s):  
S. K. Gan ◽  
K. Samaras ◽  
C. H. Thompson ◽  
E. W. Kraegen ◽  
A. Carr ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Insulin Action ◽  
Abdominal Fat ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor

Identification of the Differentially Expressed Genes Involved in the Synergistic Neurotoxicity of an HIV Protease Inhibitor and Methamphetamine

2019 ◽  
Vol 17 (4) ◽  
pp. 290-303
Author(s):  
Sangsang Li ◽  
Yanfei Li ◽  
Bingpeng Deng ◽  
Jie Yan ◽  
Yong Wang
Keyword(s):  
Protease Inhibitor ◽  
Growth Inhibition ◽  
Quantitative Polymerase Chain Reaction ◽  
Differentially Expressed Gene ◽  
Antiretroviral Drugs ◽  
Differentially Expressed ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor ◽  
Dopaminergic Cells ◽  
Immunodeficiency Syndrome

Background: The abuse of psychostimulants such as methamphetamine (METH) is common in human immunodeficiency virus (HIV)-infected individuals. Acquired immunodeficiency syndrome (AIDS) patients taking METH and antiretroviral drugs could suffer severe neurologic damage and cognitive impairment. Objective: To reveal the underlying neuropathologic mechanisms of an HIV protease inhibitor (PI) combined with METH, growth-inhibition tests of dopaminergic cells and RNA sequencing were performed. Methods: A combination of METH and PI caused more growth inhibition of dopaminergic cells than METH alone or a PI alone. Furthermore, we identified differentially expressed gene (DEG) patterns in the METH vs. untreated cells (1161 genes), PI vs. untreated cells (16 genes), METH-PI vs. PI (3959 genes), and METH-PI vs. METH groups (14 genes). Results: The DEGs in the METH-PI co-treatment group were verified in the brains of a mouse model using quantitative polymerase chain reaction and were involved mostly in the regulatory functions of cell proliferation and inflammation. Conclusion: Such identification of key regulatory genes could facilitate the study of their neuroprotective potential in the users of METH and PIs.

A Practical Synthesis of (1S,2R)-1-Amino-2-indanol, a Key Component of an HIV Protease Inhibitor, Indinavir

1999 ◽  
Vol 72 (5) ◽  
pp. 1093-1100 ◽  
Author(s):  
Hiroshi Kajiro ◽  
Shuichi Mitamura ◽  
Atsunori Mori ◽  
Tamejiro Hiyama
Keyword(s):  
Protease Inhibitor ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor ◽  
Practical Synthesis

scholarly journals HIV protease inhibitor-induced cardiac dysfunction and fibrosis is mediated by platelet-derived TGF-β1 and can be suppressed by exogenous carbon monoxide

PLoS ONE ◽  
2017 ◽  
Vol 12 (10) ◽  
pp. e0187185 ◽  
Author(s):  
Jeffrey Laurence ◽  
Sonia Elhadad ◽  
Tyler Robison ◽  
Hunter Terry ◽  
Rohan Varshney ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Protease Inhibitor ◽  
Cardiac Dysfunction ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor ◽  
Tgf Β1
Sign in / Sign up

Export Citation Format

Share Document