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Metalloenzyme Modulators and Enzyme Mimics: Synthesis and Applications

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 24694

Special Issue Editors


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Guest Editor
NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, 50019 Florence, Italy
Interests: medicinal chemistry; drugs; toxicology; enzymes; X-ray crystallography

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Guest Editor
Neurofarba Department, University of Florence, Sesto Fiorentino, FI, Italy
Interests: metalloenzymes; carbonic anhydrase; medicinal chemistry; selenium; organochalcogenide comounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue addresses our understanding of different modulations of metalloenzymes and enzyme mimics in order to better understand the mechanism behind them. About one-third of all enzymes known so far are metalloenzymes, and all major six enzyme classes established by the International Union of Biochemistry, i.e., oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases, are important members among metalloenzymes, with many different functions in cells. For this reason, they are considered as important drug targets for the treatment of major human diseases. Additionally, over the last few years, we have seen important achievements regarding molecules and their ability to act as mimetics of enzymes, that is, their ability to imitate the function of natural enzymes, thus understanding their active site structure and function. This Special Issue of Molecules welcomes contributions dealing with all aspects of metalloenzymes and enzyme mimics research, including drug design, inhibitors, activators, structure–function relationship, etc.

Dr. Andrea Angeli
Dr. Fabrizio Carta
Guest Editors

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Keywords

  • Metalloenzymes
  • Enzyme mimics
  • Enzyme inhibitor
  • Enzyme activator
  • Metal-binding function

Published Papers (6 papers)

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Research

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16 pages, 3449 KiB  
Article
Inhibition Studies on Human and Mycobacterial Carbonic Anhydrases with N-((4-Sulfamoylphenyl)carbamothioyl) Amides
by Morteza Abdoli, Alessandro Bonardi, Niccolò Paoletti, Ashok Aspatwar, Seppo Parkkila, Paola Gratteri, Claudiu T. Supuran and Raivis Žalubovskis
Molecules 2023, 28(10), 4020; https://doi.org/10.3390/molecules28104020 - 11 May 2023
Cited by 3 | Viewed by 1336
Abstract
A library of structurally diverse N-((4-sulfamoylphenyl)carbamothioyl) amides was synthesized by selective acylation of easily accessible 4-thioureidobenzenesulfonamide with various aliphatic, benzylic, vinylic and aromatic acyl chlorides under mild conditions. Inhibition of three α-class cytosolic human (h) carbonic anhydrases (CAs) (EC 4.2.1.1); that is, [...] Read more.
A library of structurally diverse N-((4-sulfamoylphenyl)carbamothioyl) amides was synthesized by selective acylation of easily accessible 4-thioureidobenzenesulfonamide with various aliphatic, benzylic, vinylic and aromatic acyl chlorides under mild conditions. Inhibition of three α-class cytosolic human (h) carbonic anhydrases (CAs) (EC 4.2.1.1); that is, hCA I, hCA II and hCA VII and three bacterial β-CAs from Mycobacterium tuberculosis (MtCA1-MtCA3) with these sulfonamides was thereafter investigated in vitro and in silico. Many of the evaluated compounds displayed better inhibition against hCA I (KI = 13.3–87.6 nM), hCA II (KI = 5.3–384.3 nM), and hCA VII (KI = 1.1–13.5 nM) compared with acetazolamide (AAZ) as the control drug (KI values of 250, 12.5 and 2.5 nM, respectively, against hCA I, hCA II and hCA VII). The mycobacterial enzymes MtCA1 and MtCA2 were also effectively inhibited by these compounds. MtCA3 was, on the other hand, poorly inhibited by the sulfonamides reported here. The most sensitive mycobacterial enzyme to these inhibitors was MtCA2 in which 10 of the 12 evaluated compounds showed KIs (KI, the inhibitor constant) in the low nanomolar range. Full article
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14 pages, 3094 KiB  
Article
Hypoxia-Activated Prodrug Derivatives of Carbonic Anhydrase Inhibitors in Benzenesulfonamide Series: Synthesis and Biological Evaluation
by Emilie Anduran, Ashok Aspatwar, Nanda-Kumar Parvathaneni, Dennis Suylen, Silvia Bua, Alessio Nocentini, Seppo Parkkila, Claudiu T. Supuran, Ludwig Dubois, Philippe Lambin and Jean-Yves Winum
Molecules 2020, 25(10), 2347; https://doi.org/10.3390/molecules25102347 - 18 May 2020
Cited by 9 | Viewed by 3391
Abstract
Hypoxia, a common feature of solid tumours’ microenvironment, is associated with an aggressive phenotype and is known to cause resistance to anticancer chemo- and radiotherapies. Tumour-associated carbonic anhydrases isoform IX (hCA IX), which is upregulated under hypoxia in many malignancies participating to the [...] Read more.
Hypoxia, a common feature of solid tumours’ microenvironment, is associated with an aggressive phenotype and is known to cause resistance to anticancer chemo- and radiotherapies. Tumour-associated carbonic anhydrases isoform IX (hCA IX), which is upregulated under hypoxia in many malignancies participating to the microenvironment acidosis, represents a valuable target for drug strategy against advanced solid tumours. To overcome cancer cell resistance and improve the efficacy of therapeutics, the use of bio-reducible prodrugs also known as Hypoxia-activated prodrugs (HAPs), represents an interesting strategy to be applied to target hCA IX isozyme through the design of selective carbonic anhydrase IX inhibitors (CAIs). Here, we report the design, synthesis and biological evaluations including CA inhibition assays, toxicity assays on zebrafish and viability assays on human cell lines (HT29 and HCT116) of new HAP-CAIs, harboring different bio-reducible moieties in nitroaromatic series and a benzenesulfonamide warhead to target hCA IX. The CA inhibition assays of this compound series showed a slight selectivity against hCA IX versus the cytosolic off-target hCA II and hCA I isozymes. Toxicity and viability assays have highlighted that the compound bearing the 2-nitroimidazole moiety possesses the lowest toxicity (LC50 of 1400 µM) and shows interesting results on viability assays. Full article
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9 pages, 1522 KiB  
Article
Crystal Structure of a Tetrameric Type II β-Carbonic Anhydrase from the Pathogenic Bacterium Burkholderia pseudomallei
by Andrea Angeli, Marta Ferraroni, Mariana Pinteala, Stelian S. Maier, Bogdan C. Simionescu, Fabrizio Carta, Sonia Del Prete, Clemente Capasso and Claudiu T. Supuran
Molecules 2020, 25(10), 2269; https://doi.org/10.3390/molecules25102269 - 12 May 2020
Cited by 10 | Viewed by 2375
Abstract
Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate and proton. Currently, CA inhibitors are widely used as antiglaucoma, anticancer, and anti-obesity drugs and for the treatment of neurological disorders. Recently, the potential use of [...] Read more.
Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate and proton. Currently, CA inhibitors are widely used as antiglaucoma, anticancer, and anti-obesity drugs and for the treatment of neurological disorders. Recently, the potential use of CA inhibitors to fight infections caused by protozoa, fungi, and bacteria has emerged as a new research line. In this article, the X-ray crystal structure of β-CA from Burkholderia pseudomallei was reported. The X-ray crystal structure of this new enzyme was solved at 2.7 Å resolution, revealing a tetrameric type II β-CA with a “closed” active site in which the zinc is tetrahedrally coordinated to Cys46, Asp48, His102, and Cys105. B. pseudomallei is known to encode at least two CAs, a β-CA, and a γ-CA. These proteins, playing a pivotal role in its life cycle and pathogenicity, offer a novel therapeutic opportunity to obtain antibiotics with a different mechanism of action. Furthermore, the new structure can provide a clear view of the β-CA mechanism of action and the possibility to find selective inhibitors for this class of CAs. Full article
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Review

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25 pages, 5912 KiB  
Review
Amine- and Amino Acid-Based Compounds as Carbonic Anhydrase Activators
by Andrea Angeli, Emanuela Berrino, Simone Carradori, Claudiu T. Supuran, Marzia Cirri, Fabrizio Carta and Gabriele Costantino
Molecules 2021, 26(23), 7331; https://doi.org/10.3390/molecules26237331 - 2 Dec 2021
Cited by 8 | Viewed by 2520
Abstract
After being rather neglected as a research field in the past, carbonic anhydrase activators (CAAs) were undoubtedly demonstrated to be useful in diverse pharmaceutical and industrial applications. They also improved the knowledge of the requirements to selectively interact with a CA isoform over [...] Read more.
After being rather neglected as a research field in the past, carbonic anhydrase activators (CAAs) were undoubtedly demonstrated to be useful in diverse pharmaceutical and industrial applications. They also improved the knowledge of the requirements to selectively interact with a CA isoform over the others and confirmed the catalytic mechanism of this class of compounds. Amino acid and amine derivatives were the most explored in in vitro, in vivo and crystallographic studies as CAAs. Most of them were able to activate human or non-human CA isoforms in the nanomolar range, being proposed as therapeutic and industrial tools. Some isoforms are better activated by amino acids than amines derivatives and the stereochemistry may exert a role. Finally, non-human CAs have been very recently tested for activation studies, paving the way to innovative industrial and environmental applications. Full article
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25 pages, 6630 KiB  
Review
Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge
by Francesca Picarazzi, Ilaria Vicenti, Francesco Saladini, Maurizio Zazzi and Mattia Mori
Molecules 2020, 25(23), 5695; https://doi.org/10.3390/molecules25235695 - 3 Dec 2020
Cited by 60 | Viewed by 10564
Abstract
The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by [...] Read more.
The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses’ story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches. Full article
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14 pages, 911 KiB  
Review
Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery
by Felipe Raposo Passos Mansoldo, Fabrizio Carta, Andrea Angeli, Veronica da Silva Cardoso, Claudiu T. Supuran and Alane Beatriz Vermelho
Molecules 2020, 25(22), 5483; https://doi.org/10.3390/molecules25225483 - 23 Nov 2020
Cited by 29 | Viewed by 3237
Abstract
Chagas disease still has no effective treatment option for all of its phases despite being discovered more than 100 years ago. The development of commercial drugs has been stagnating since the 1960s, a fact that sheds light on the question of how drug [...] Read more.
Chagas disease still has no effective treatment option for all of its phases despite being discovered more than 100 years ago. The development of commercial drugs has been stagnating since the 1960s, a fact that sheds light on the question of how drug discovery research has progressed and taken advantage of technological advances. Could it be that technological advances have not yet been sufficient to resolve this issue or is there a lack of protocol, validation and standardization of the data generated by different research teams? This work presents an overview of commercial drugs and those that have been evaluated in studies and clinical trials so far. A brief review is made of recent target-based and phenotypic studies based on the search for molecules with anti-Trypanosoma cruzi action. It also discusses how proteochemometric (PCM) modeling and microcrystal electron diffraction (MicroED) can help in the case of the lack of a 3D protein structure; more specifically, Trypanosoma cruzi carbonic anhydrase. Full article
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