Cargando…

In Search of Differential Inhibitors of Aldose Reductase

Aldose reductase, classified within the aldo-keto reductase family as AKR1B1, is an NADPH dependent enzyme that catalyzes the reduction of hydrophilic as well as hydrophobic aldehydes. AKR1B1 is the first enzyme of the so-called polyol pathway that allows the conversion of glucose into sorbitol, whi...

Descripción completa

Detalles Bibliográficos
Autores principales: Balestri, Francesco, Moschini, Roberta, Mura, Umberto, Cappiello, Mario, Del Corso, Antonella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024650/
https://www.ncbi.nlm.nih.gov/pubmed/35454074
http://dx.doi.org/10.3390/biom12040485
_version_ 1784690654543085568
author Balestri, Francesco
Moschini, Roberta
Mura, Umberto
Cappiello, Mario
Del Corso, Antonella
author_facet Balestri, Francesco
Moschini, Roberta
Mura, Umberto
Cappiello, Mario
Del Corso, Antonella
author_sort Balestri, Francesco
collection PubMed
description Aldose reductase, classified within the aldo-keto reductase family as AKR1B1, is an NADPH dependent enzyme that catalyzes the reduction of hydrophilic as well as hydrophobic aldehydes. AKR1B1 is the first enzyme of the so-called polyol pathway that allows the conversion of glucose into sorbitol, which in turn is oxidized to fructose by sorbitol dehydrogenase. The activation of the polyol pathway in hyperglycemic conditions is generally accepted as the event that is responsible for a series of long-term complications of diabetes such as retinopathy, cataract, nephropathy and neuropathy. The role of AKR1B1 in the onset of diabetic complications has made this enzyme the target for the development of molecules capable of inhibiting its activity. Virtually all synthesized compounds have so far failed as drugs for the treatment of diabetic complications. This failure may be partly due to the ability of AKR1B1 to reduce alkenals and alkanals, produced in oxidative stress conditions, thus acting as a detoxifying agent. In recent years we have proposed an alternative approach to the inhibition of AKR1B1, suggesting the possibility of a differential inhibition of the enzyme through molecules able to preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. The rationale and examples of this new generation of aldose reductase differential inhibitors (ARDIs) are presented.
format Online
Article
Text
id pubmed-9024650
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-90246502022-04-23 In Search of Differential Inhibitors of Aldose Reductase Balestri, Francesco Moschini, Roberta Mura, Umberto Cappiello, Mario Del Corso, Antonella Biomolecules Review Aldose reductase, classified within the aldo-keto reductase family as AKR1B1, is an NADPH dependent enzyme that catalyzes the reduction of hydrophilic as well as hydrophobic aldehydes. AKR1B1 is the first enzyme of the so-called polyol pathway that allows the conversion of glucose into sorbitol, which in turn is oxidized to fructose by sorbitol dehydrogenase. The activation of the polyol pathway in hyperglycemic conditions is generally accepted as the event that is responsible for a series of long-term complications of diabetes such as retinopathy, cataract, nephropathy and neuropathy. The role of AKR1B1 in the onset of diabetic complications has made this enzyme the target for the development of molecules capable of inhibiting its activity. Virtually all synthesized compounds have so far failed as drugs for the treatment of diabetic complications. This failure may be partly due to the ability of AKR1B1 to reduce alkenals and alkanals, produced in oxidative stress conditions, thus acting as a detoxifying agent. In recent years we have proposed an alternative approach to the inhibition of AKR1B1, suggesting the possibility of a differential inhibition of the enzyme through molecules able to preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. The rationale and examples of this new generation of aldose reductase differential inhibitors (ARDIs) are presented. MDPI 2022-03-22 /pmc/articles/PMC9024650/ /pubmed/35454074 http://dx.doi.org/10.3390/biom12040485 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Balestri, Francesco
Moschini, Roberta
Mura, Umberto
Cappiello, Mario
Del Corso, Antonella
In Search of Differential Inhibitors of Aldose Reductase
title In Search of Differential Inhibitors of Aldose Reductase
title_full In Search of Differential Inhibitors of Aldose Reductase
title_fullStr In Search of Differential Inhibitors of Aldose Reductase
title_full_unstemmed In Search of Differential Inhibitors of Aldose Reductase
title_short In Search of Differential Inhibitors of Aldose Reductase
title_sort in search of differential inhibitors of aldose reductase
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9024650/
https://www.ncbi.nlm.nih.gov/pubmed/35454074
http://dx.doi.org/10.3390/biom12040485
work_keys_str_mv AT balestrifrancesco insearchofdifferentialinhibitorsofaldosereductase
AT moschiniroberta insearchofdifferentialinhibitorsofaldosereductase
AT muraumberto insearchofdifferentialinhibitorsofaldosereductase
AT cappiellomario insearchofdifferentialinhibitorsofaldosereductase
AT delcorsoantonella insearchofdifferentialinhibitorsofaldosereductase