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Biomolecules
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Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms
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Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Enzymology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 13628

Special Issue Editor

Dr. Mario Cappiello

E-Mail Website
Guest Editor
Associate Professor, Biochemistry Unit, Department of Biology, University of Pisa, 56126 Pisa, Italy
Interests: protein biochemistry; protein purification; enzymes; enzyme kinetics; enzyme inhibition; oxidative stress; aldose reductase
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since its discovery, aldose reductase (AKR1B1), an enzyme of the aldo-keto reductase family that catalyzes the NADPH reduction of a variety of hydrophilic as well as hydrophobic aldehydes, has been considered a promising target for the treatment of long-term diabetic complications. This enzyme is the first one in the so-called polyol pathway, which converts glucose into fructose. Under hyperglycemic conditions, an exaggerated flux of glucose through the polyol pathway leads to a series of damaging events (e.g., sorbitol accumulation, oxidative stress, protein glycation) involved in the etiology of secondary diabetic complications, such as nephropathies, retinopathies, neuropathies, and cataract. Over the last four decades, a great effort has been devoted to the search of molecules able to inhibit aldose reductase, thus preventing the onset of diabetic complications. Despite the in vitro efficiency of many molecules synthetized as aldose reductase inhibitors, no significant drug development has followed. There may be a number of reasons for such a failure, from the reduced bioavailability of the drug to the onset of unwanted side effects; however, another possible explanation lies on the catalytic features of the enzyme itself, which can reduce toxic alkenals and alkanals, derived from lipid peroxidation processes, thus behaving as a detoxifying enzyme.

In addition to its possible role in the etiology of diabetic complications, another relevant feature of aldose reductase which has emerged more recently is its involvement in inflammation: Several studies have suggested that aldose reductase may play a key role in a number of inflammatory processes through the production of pro-inflammatory molecules. Thus, the inhibition of the enzyme activity may help to control inflammation.

This Special Issue will focus on the functions, inhibition, and molecular mechanisms of aldose reductase and will include reviews and research articles on these topics with the aim of presenting the most recent advances on the features of this multifaceted enzyme.

Prof. Mario Cappiello
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aldose reductase
  • AKR1B1
  • aldo-keto reductases
  • polyol pathway
  • 4 hydroxynonenal
  • aldose reductase inhibitors
  • diabetes
  • inflammation

Published Papers (4 papers)

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Research

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27 pages, 4788 KiB  
Article
Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress
by Lidia Ciccone, Giovanni Petrarolo, Francesca Barsuglia, Carole Fruchart-Gaillard, Evelyne Cassar Lajeunesse, Adeniyi T. Adewumi, Mahmoud E. S. Soliman, Concettina La Motta, Elisabetta Orlandini and Susanna Nencetti
Biomolecules 2022, 12(3), 448; https://doi.org/10.3390/biom12030448 - 14 Mar 2022
Cited by 13 | Viewed by 2933
Abstract
Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is [...] Read more.
Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of diabetic complications. Herein we describe a novel series of (E)-benzaldehyde O-benzyl oximes 6a–e, 7a–e, 8a–e, and 9–11 as ALR2 inhibitors endowed with anti-oxidant properties. Inspired by the natural products, the synthesized derivatives are characterized by a different polyhydroxy substitution pattern on their benzaldehyde fragment, which proved crucial for both the enzyme inhibitory activity and the anti-oxidant capacity. Derivatives (E)-2,3,4-trihydroxybenzaldehyde O-(3-methoxybenzyl) oxime (7b) and (E)-2,3,4-trihydroxybenzaldehyde O-(4-methoxybenzyl) oxime (8b) turned out to be the most effective dual-acting products, proving to combine the best ALR2 inhibitory properties with significant anti-oxidant efficacy. Full article
(This article belongs to the Special Issue Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms)
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21 pages, 6639 KiB  
Article
Which Properties Allow Ligands to Open and Bind to the Transient Binding Pocket of Human Aldose Reductase?
by Anna Sandner, Khang Ngo, Christoph P. Sager, Frithjof Scheer, Michael Daude, Wibke E. Diederich, Andreas Heine and Gerhard Klebe
Biomolecules 2021, 11(12), 1837; https://doi.org/10.3390/biom11121837 - 6 Dec 2021
Cited by 6 | Viewed by 2865
Abstract
The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to [...] Read more.
The transient specificity pocket of aldose reductase only opens in response to specific ligands. This pocket may offer an advantage for the development of novel, more selective ligands for proteins with similar topology that lack such an adaptive pocket. Our aim was to elucidate which properties allow an inhibitor to bind in the specificity pocket. A series of inhibitors that share the same parent scaffold but differ in their attached aromatic substituents were screened using ITC and X-ray crystallography for their ability to occupy the pocket. Additionally, we investigated the electrostatic potentials and charge distribution across the attached terminal aromatic groups with respect to their potential to bind to the transient pocket of the enzyme using ESP calculations. These methods allowed us to confirm the previously established hypothesis that an electron-deficient aromatic group is an important prerequisite for opening and occupying the specificity pocket. We also demonstrated from our crystal structures that a pH shift between 5 and 8 does not affect the binding position of the ligand in the specificity pocket. This allows for a comparison between thermodynamic and crystallographic data collected at different pH values. Full article
(This article belongs to the Special Issue Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms)
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12 pages, 1312 KiB  
Article
Nanogel-Facilitated In-Situ Delivery of a Cataract Inhibitor
by Dixa Gautam, Michelle G. Pedler, Devatha P. Nair and Jonathan Mark Petrash
Biomolecules 2021, 11(8), 1150; https://doi.org/10.3390/biom11081150 - 4 Aug 2021
Cited by 6 | Viewed by 2118
Abstract
Cataracts are a leading cause of blindness worldwide. Surgical removal of cataracts is a safe and effective procedure to restore vision. However, a large number of patients later develop vision loss due to regrowth of lens cells and subsequent degradation of the visual [...] Read more.
Cataracts are a leading cause of blindness worldwide. Surgical removal of cataracts is a safe and effective procedure to restore vision. However, a large number of patients later develop vision loss due to regrowth of lens cells and subsequent degradation of the visual axis leading to visual disability. This postsurgical complication, known as posterior capsular opacification (PCO), occurs in up to 30% of cataract patients and has no clinically proven pharmacological means of prevention. Despite the availability of many compounds capable of preventing early steps in PCO development, there is currently no effective means to deliver such therapies into the eye for a suitable duration. To model a solution to this unmet medical need, we fabricated acrylic substrates as intraocular lens (IOL) mimics scaled to place into the capsular bag of the mouse lens following a mock-cataract surgery. Substrates were coated with a hydrophilic crosslinked acrylate nanogel designed to elute Sorbinil, an aldose reductase inhibitor previously shown to suppress PCO. Insertion of the Sorbinil-eluting device into the lens capsule at the time of cataract surgery resulted in substantial prevention of cellular changes associated with PCO development. This model demonstrates that a cataract inhibitor can be delivered into the postsurgical lens capsule at therapeutic levels. Full article
(This article belongs to the Special Issue Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms)
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Review

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12 pages, 1809 KiB  
Review
In Search of Differential Inhibitors of Aldose Reductase
by Francesco Balestri, Roberta Moschini, Umberto Mura, Mario Cappiello and Antonella Del Corso
Biomolecules 2022, 12(4), 485; https://doi.org/10.3390/biom12040485 - 22 Mar 2022
Cited by 23 | Viewed by 3920
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms)
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