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Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 25139

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Prof. Dr. Phaedra Eleftheriou

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Department of Medical Laboratories, School of Health and Care Professions, Alexander Technological Educational Institute of Thessaloniki, 54700 Thessaloniki, Greece
Interests: Enzymes and enzyme inhibitors in Diagnosis and Therapy; Phosphatase Inhibitors(SHP-2 (JMML), PTP1B, LAR (Diabetes II)); Squalene synthase inhibitors(SQS (dyslipidemia) inhibitors of COX-1/2, LOX (anti-inflammatory agents), HIV-1 reverse transcriptase and integrase inhibitors); Computer-Aided Rational design of specific enzyme inhibitors with application in Diagnosis and Therapy; Correlation of biochemical markers with disease pathophysiology

Prof. Dr. Athina Geronikaki

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Guest Editor

School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
Interests: biologically active heterocycles; thiazole; thiazolidinone; benzothiazole; thiadiazoles with antimicrobial activity; COX/LOX, PTP1b, HIV RT enzyme inhibitors; anti inflammatory
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Special Issue Information

Dear Colleagues,

This Special Issue aims to gather research and review articles on enzymes and enzyme inhibitors with applications in diagnosis and therapy, covering a vast area of medical research.

As enzymes are involved in all biochemical processes, there are numerous pathological disorders related to the deficiency, malfunction, reduced/increased activity or overexpression of enzymes. In addition, deficiencies of enzyme inhibitors are also responsible for serious diseases. Therefore, the study of enzymes and their inhibitors is crucial for the elucidation of the pathophysiology of diseases and the exploration of therapeutic strategies, representing a great area of continuous research.

The role of enzymes in the regulation of all processes has turned them into important drug targets. Enzyme inhibitors constitute the second-greatest drug category, following receptor agonists and antagonists. Enzyme inhibitors are among the drugs used for the treatment of metabolic and degenerative diseases including hypercholesterolemia, diabetes and hypertension as well as antimicrobial and antiviral therapy. The large number of isoenzymes necessitates the development of highly specific and effective inhibitors in order to achieve target effects with fewer undesired side effects. This goal leads to the continuation of research for the development of novel and improved inhibitors, even for old enzyme targets, while the development of resistant strains in antimicrobial and antiviral therapy underlines the continuous need for novel inhibitors and novel targets.

In the field of diagnosis, enzymes constitute important biomolecules. The levels of several enzymes and specific isoenzymes are measured for the diagnosis and monitoring of diseases. Although specific isoenzyme inhibitors enable the differential measurement of organ-specific isoenzymes in some cases, such effective inhibitors have not been found for most of the enzymes. On the other hand, the number of enzymes and related methods being used in enzymatic assays for the measurement of other biomarkers in classic methods, dry chemistry and bioelectrode-based techniques is increasing.

We call you to contribute to this Special Issue by submitting your research as well as review articles in the field.

Prof. Dr. Phaedra Eleftheriou
Prof. Dr. Athina Geronikaki
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

enzyme
enzyme inhibitor
drug target
enzyme deficiency
enzyme overexpression
biomarker
drugs
diagnosis
therapy

Published Papers (9 papers)

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Editorial

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3 pages, 194 KiB

Open AccessEditorial

Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis

by Athina Geronikaki and Phaedra T. Eleutheriou

Int. J. Mol. Sci. 2023, 24(6), 5245; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065245 - 09 Mar 2023

Cited by 2 | Viewed by 1329

Abstract

This is the first part of a Special Issue on enzymes and enzymes inhibitors and their applications in medicine and diagnosis [...] Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

Research

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14 pages, 1275 KiB

Open AccessArticle

Advances in Membrane-Bound Catechol-O-Methyltransferase Stability Achieved Using a New Ionic Liquid-Based Storage Formulation

by Ana M. Gonçalves, Ângela Sousa, Augusto Q. Pedro, Maria J. Romão, João A. Queiroz, Eugénia Gallardo and Luís A. Passarinha

Int. J. Mol. Sci. 2022, 23(13), 7264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137264 - 30 Jun 2022

Cited by 6 | Viewed by 1840

Abstract

Membrane-bound catechol-O-methyltransferase (MBCOMT), present in the brain and involved in the main pathway of the catechol neurotransmitter deactivation, is linked to several types of human dementia, which are relevant pharmacological targets for new potent and nontoxic inhibitors that have been developed, particularly for Parkinson’s disease treatment. However, the inexistence of an MBCOMT 3D-structure presents a blockage in new drugs’ design and clinical studies due to its instability. The enzyme has a clear tendency to lose its biological activity in a short period of time. To avoid the enzyme sequestering into a non-native state during the downstream processing, a multi-component buffer plays a major role, with the addition of additives such as cysteine, glycerol, and trehalose showing promising results towards minimizing hMBCOMT damage and enhancing its stability. In addition, ionic liquids, due to their virtually unlimited choices for cation/anion paring, are potential protein stabilizers for the process and storage buffers. Screening experiments were designed to evaluate the effect of distinct cation/anion ILs interaction in hMBCOMT enzymatic activity. The ionic liquids: choline glutamate [Ch][Glu], choline dihydrogen phosphate ([Ch][DHP]), choline chloride ([Ch]Cl), 1- dodecyl-3-methylimidazolium chloride ([C12mim]Cl), and 1-butyl-3-methylimidazolium chloride ([C4mim]Cl) were supplemented to hMBCOMT lysates in a concentration from 5 to 500 mM. A major potential stabilizing effect was obtained using [Ch][DHP] (10 and 50 mM). From the DoE 146% of hMBCOMT activity recovery was obtained with [Ch][DHP] optimal conditions (7.5 mM) at −80 °C during 32.4 h. These results are of crucial importance for further drug development once the enzyme can be stabilized for longer periods of time. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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16 pages, 1648 KiB

Open AccessArticle

Elevation of Tear MMP-9 Concentration as a Biomarker of Inflammation in Ocular Pathology by Antibody Microarray Immunodetection Assays

by Miguel de la Fuente, Iñaki Rodríguez-Agirretxe, Elena Vecino, Egoitz Astigarraga, Arantxa Acera and Gabriel Barreda-Gómez

Int. J. Mol. Sci. 2022, 23(10), 5639; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105639 - 18 May 2022

Cited by 8 | Viewed by 2115

Abstract

Matrix metalloproteinases are a family of enzymes fundamental in inflammatory processes. Between them, MMP-9 is up-regulated during inflammation; thus, its quantification in non-invasive fluids is a promising approach for inflammation identification. To this goal, a biomarker quantification test was developed for ocular inflammation detection using anti-MMP-9 antibody microarrays (AbMAs). After validation with eight healthy control tear samples characterized by ELISA, 20 samples were tested from individuals diagnosed with ocular inflammation due to: cataracts, glaucoma, meibomian gland dysfunction, allergy, or dry eye. Concentration values of tear MMP-9 were obtained for each sample, and 12 patients surpassed the pathological threshold (30 ng/mL). A significant elevation of MMP-9 concentration in the tears of glaucoma patients compared with healthy controls was observed. In order to evaluate the diagnostic ability, an ROC curve analysis was performed using our data, determining the optimal threshold for the test at 33.6 ng/mL of tear MMP-9. In addition, a confusion matrix was applied, estimating sensitivity at 60%, specificity at 88%, and accuracy at 68%. In conclusion, we demonstrated that the AbMAs system allows the quantification of MMP-9 in pathologies that involve inflammation of the ocular surface. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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16 pages, 41691 KiB

Open AccessArticle

Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches

by Gyutae Lim, Ka Young You, Jeong Hyun Lee, Moon Kook Jeon, Byung Ho Lee, Jae Yong Ryu and Kwang-Seok Oh

Int. J. Mol. Sci. 2022, 23(7), 3807; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073807 - 30 Mar 2022

Cited by 5 | Viewed by 2560

Abstract

Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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23 pages, 5416 KiB

Open AccessArticle

Hexokinase 2 Inhibition and Biological Effects of BNBZ and Its Derivatives: The Influence of the Number and Arrangement of Hydroxyl Groups

by Karolina Juszczak, Anna Kubicka, Radosław Kitel, Grzegorz Dzido, Magdalena Łabieniec-Watała, Serafin Zawadzki, Agnieszka Marczak, Krzysztof Walczak, Karolina Matczak and Mateusz D. Tomczyk

Int. J. Mol. Sci. 2022, 23(5), 2616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052616 - 27 Feb 2022

Cited by 6 | Viewed by 2517

Abstract

Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b–2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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16 pages, 3411 KiB

Open AccessArticle

Novel Aurora A Kinase Inhibitor Fangchinoline Enhances Cisplatin–DNA Adducts and Cisplatin Therapeutic Efficacy in OVCAR-3 Ovarian Cancer Cells-Derived Xenograft Model

by Daniel Winardi, Pei-Yi Chu, Guan-Yu Chen, Ke Wang, Wei-Yu Hsu, Ching-Liang Hsieh, Yung-Hsiang Chen, Yang-Chang Wu and Juan-Cheng Yang

Int. J. Mol. Sci. 2022, 23(3), 1868; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031868 - 07 Feb 2022

Cited by 4 | Viewed by 2241

Abstract

Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin–DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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15 pages, 3535 KiB

Open AccessArticle

Molecular Elucidation of a Urate Oxidase from Deinococcus radiodurans for Hyperuricemia and Gout Therapy

by Yi-Chih Chiu, Ting-Syuan Hsu, Chen-Yu Huang and Chun-Hua Hsu

Int. J. Mol. Sci. 2021, 22(11), 5611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115611 - 25 May 2021

Cited by 8 | Viewed by 2656

Abstract

Urate oxidase initiates the uric acid degradation pathways and is extensively used for protein drug development for gout therapy and serum uric acid diagnosis. We first present the biochemical and structural elucidation of a urate oxidase from the extremophile microorganism Deinococcus radiodurans (DrUox). From enzyme characterization, DrUox showed optimal catalytic ability at 30 °C and pH 9.0 with high stability under physiological conditions. Only the Mg²⁺ ion moderately elevated its activity, which indicates the characteristic of the cofactor-free urate oxidase family. Of note, DrUox is thermostable in mesophilic conditions. It retains almost 100% activity when incubated at 25 °C and 37 °C for 24 h. In this study, we characterized a thermostable urate oxidase, DrUox with high catalytic efficiency and thermal stability, which strengthens its potential for medical applications. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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Review

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23 pages, 7246 KiB

Open AccessReview

Developing New Treatments for COVID-19 through Dual-Action Antiviral/Anti-Inflammatory Small Molecules and Physiologically Based Pharmacokinetic Modeling

by Panagiotis Zagaliotis, Anthi Petrou, George A. Mystridis, Athina Geronikaki, Ioannis S. Vizirianakis and Thomas J. Walsh

Int. J. Mol. Sci. 2022, 23(14), 8006; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23148006 - 20 Jul 2022

Cited by 3 | Viewed by 2483

Abstract

Broad-spectrum antiviral agents that are effective against many viruses are difficult to develop, as the key molecules, as well as the biochemical pathways by which they cause infection, differ largely from one virus to another. This was more strongly highlighted by the COVID-19 pandemic, which found health systems all over the world largely unprepared and proved that the existing armamentarium of antiviral agents is not sufficient to address viral threats with pandemic potential. The clinical protocols for the treatment of COVID-19 are currently based on the use of inhibitors of the inflammatory cascade (dexamethasone, baricitinib), or inhibitors of the cytopathic effect of the virus (monoclonal antibodies, molnupiravir or nirmatrelvir/ritonavir), using different agents. There is a critical need for an expanded armamentarium of orally bioavailable small-molecular medicinal agents, including those that possess dual antiviral and anti-inflammatory (AAI) activity that would be readily available for the early treatment of mild to moderate COVID-19 in high-risk patients. A multidisciplinary approach that involves the use of in silico screening tools to identify potential drug targets of an emerging pathogen, as well as in vitro and in vivo models for the determination of a candidate drug’s efficacy and safety, are necessary for the rapid and successful development of antiviral agents with potentially dual AAI activity. Characterization of candidate AAI molecules with physiologically based pharmacokinetics (PBPK) modeling would provide critical data for the accurate dosing of new therapeutic agents against COVID-19. This review analyzes the dual mechanisms of AAI agents with potential anti-SARS-CoV-2 activity and discusses the principles of PBPK modeling as a conceptual guide to develop new pharmacological modalities for the treatment of COVID-19. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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33 pages, 2398 KiB

Open AccessReview

Characteristics of Food Protein-Derived Antidiabetic Bioactive Peptides: A Literature Update

by Nhung Thi Phuong Nong and Jue-Liang Hsu

Int. J. Mol. Sci. 2021, 22(17), 9508; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179508 - 01 Sep 2021

Cited by 20 | Viewed by 4780

Abstract

Diabetes, a glucose metabolic disorder, is considered one of the biggest challenges associated with a complex complication of health crises in the modern lifestyle. Inhibition or reduction of the dipeptidyl peptidase IV (DPP-IV), alpha-glucosidase, and protein-tyrosine phosphatase 1B (PTP-1B) enzyme activities or expressions are notably considered as the promising therapeutic strategies for the management of type 2 diabetes (T2D). Various food protein-derived antidiabetic bioactive peptides have been isolated and verified. This review provides an overview of the DPP-IV, PTP-1B, and α-glucosidase inhibitors, and updates on the methods for the discovery of DPP-IV inhibitory peptides released from food-protein hydrolysate. The finding of novel bioactive peptides involves studies about the strategy of separation fractionation, the identification of peptide sequences, and the evaluation of peptide characteristics in vitro, in silico, in situ, and in vivo. The potential of bioactive peptides suggests useful applications in the prevention and management of diabetes. Furthermore, evidence of clinical studies is necessary for the validation of these peptides’ efficiencies before commercial applications. Full article

(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis)

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