Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
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
_version_ 1783562202931789824
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
work_keys_str_mv AT diesingertorsten drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT bukovyacheslav drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT lautweinalfred drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT dvorskyradovan drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT belonovskayaelena drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT lukivskayaoksana drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT narutaelena drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT kirkosiarhei drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT andreevviktor drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT buckertdominik drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT berglersebastian drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT renzchristian drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT schneideredith drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT kuchenbauerflorian drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT kumarmukesh drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT gunescagatay drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT bucheleberthold drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT simmetthomas drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT mullerenochdieter drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT wirththomas drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis
AT haehnerthomas drugtargetingcyp2e1forthetreatmentofearlystagealcoholicsteatohepatitis