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Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis
BACKGROUND AND AIMS: Alcoholic steatohepatitis (ASH)—the inflammation of fatty liver—is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alco...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377376/ https://www.ncbi.nlm.nih.gov/pubmed/32701948 http://dx.doi.org/10.1371/journal.pone.0235990 |
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author | Diesinger, Torsten Buko, Vyacheslav Lautwein, Alfred Dvorsky, Radovan Belonovskaya, Elena Lukivskaya, Oksana Naruta, Elena Kirko, Siarhei Andreev, Viktor Buckert, Dominik Bergler, Sebastian Renz, Christian Schneider, Edith Kuchenbauer, Florian Kumar, Mukesh Günes, Cagatay Büchele, Berthold Simmet, Thomas Müller-Enoch, Dieter Wirth, Thomas Haehner, Thomas |
author_facet | Diesinger, Torsten Buko, Vyacheslav Lautwein, Alfred Dvorsky, Radovan Belonovskaya, Elena Lukivskaya, Oksana Naruta, Elena Kirko, Siarhei Andreev, Viktor Buckert, Dominik Bergler, Sebastian Renz, Christian Schneider, Edith Kuchenbauer, Florian Kumar, Mukesh Günes, Cagatay Büchele, Berthold Simmet, Thomas Müller-Enoch, Dieter Wirth, Thomas Haehner, Thomas |
author_sort | Diesinger, Torsten |
collection | PubMed |
description | BACKGROUND AND AIMS: Alcoholic steatohepatitis (ASH)—the inflammation of fatty liver—is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation—the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. METHODS: In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. RESULTS: A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. CONCLUSIONS: Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH. |
format | Online Article Text |
id | pubmed-7377376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-73773762020-08-12 Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis Diesinger, Torsten Buko, Vyacheslav Lautwein, Alfred Dvorsky, Radovan Belonovskaya, Elena Lukivskaya, Oksana Naruta, Elena Kirko, Siarhei Andreev, Viktor Buckert, Dominik Bergler, Sebastian Renz, Christian Schneider, Edith Kuchenbauer, Florian Kumar, Mukesh Günes, Cagatay Büchele, Berthold Simmet, Thomas Müller-Enoch, Dieter Wirth, Thomas Haehner, Thomas PLoS One Research Article BACKGROUND AND AIMS: Alcoholic steatohepatitis (ASH)—the inflammation of fatty liver—is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation—the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. METHODS: In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. RESULTS: A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. CONCLUSIONS: Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH. Public Library of Science 2020-07-23 /pmc/articles/PMC7377376/ /pubmed/32701948 http://dx.doi.org/10.1371/journal.pone.0235990 Text en © 2020 Diesinger et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Diesinger, Torsten Buko, Vyacheslav Lautwein, Alfred Dvorsky, Radovan Belonovskaya, Elena Lukivskaya, Oksana Naruta, Elena Kirko, Siarhei Andreev, Viktor Buckert, Dominik Bergler, Sebastian Renz, Christian Schneider, Edith Kuchenbauer, Florian Kumar, Mukesh Günes, Cagatay Büchele, Berthold Simmet, Thomas Müller-Enoch, Dieter Wirth, Thomas Haehner, Thomas Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis |
title | Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis |
title_full | Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis |
title_fullStr | Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis |
title_full_unstemmed | Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis |
title_short | Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis |
title_sort | drug targeting cyp2e1 for the treatment of early-stage alcoholic steatohepatitis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377376/ https://www.ncbi.nlm.nih.gov/pubmed/32701948 http://dx.doi.org/10.1371/journal.pone.0235990 |
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