Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 43585

Share This Special Issue

Special Issue Editor

Prof. Dr. Claudiu T. Supuran

E-Mail Website
Guest Editor

Neurofarba Department, Section of Farmaceutical and Neutraceutical Sciences, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteases and carbonic anhydrases are among the most widespread enzymes in organisms all over the phylogenetic tree, in which they play crucial physiological roles. Dysregulation of their activity is connected with many diseases, such as tumors, viral infections, blood coagulation disorders, digestive diseases, etc. Protease inhibitors targeting all classes of such known enzymes are widely used as antivirals (against HIV and hepatitis C infections), antithromodotics (targeting serine proteases involved in the blood coagulation cascade), whereas inhibitors of other proteases, such as matrix metalloproteinases, have found fewer applications due to their toxicity problems. Carbonic anhydrase inhibitors, on the other hand, are used as antiglaucoma, antiepileptic, antiobesity, and as diuretic drugs, whereas newer applications target metastatic tumors, both for treatment and imaging, with one small molecule and one antibody in advanced clinical trials. Antiinfectives, based on inhibition of carbonic anhydrases from pathogenic bacteria, fungi, and protozoa, have also begun to be investigated. The present Special Issue of the International Journal of Molecular Sciences welcomes contributions dealing with all aspects connected to the chemistry, biochemistry, pharmacology and toxicology of this important class of enzyme inhibitors.

Prof. Dr. Claudiu T. Supuran
Guest Editor

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

carbonic anhydrase
protease
inhibitor
antiviral drug
antitumor drug
drug design
serine protease
metalloprotease
aspartic protease

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (9 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

15 pages, 1280 KiB

Open AccessArticle

NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease

by Aisha S. Ahmed, Svante Berg, Kanar Alkass, Henrik Druid, David A. Hart, Camilla I. Svensson and Eva Kosek

Int. J. Mol. Sci. 2019, 20(3), 658; https://doi.org/10.3390/ijms20030658 - 3 Feb 2019

Cited by 32 | Viewed by 4534

Abstract

The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. RELA, NFKB1, CGRP, TAC1, TRPV1, and MMP-3 gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1–DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1–DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1–DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1–DNA binding was positively associated with TRPV1 and MMP-3 gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Figure 1

12 pages, 1038 KiB

Open AccessArticle

Carbonic Anhydrase Inhibitors of Different Structures Dilate Pre-Contracted Porcine Retinal Arteries

by Thor Eysteinsson, Hrönn Gudmundsdottir, Arnar Oessur Hardarson, Emanuela Berrino, Silvia Selleri, Claudiu T. Supuran and Fabrizio Carta

Int. J. Mol. Sci. 2019, 20(3), 467; https://doi.org/10.3390/ijms20030467 - 22 Jan 2019

Cited by 9 | Viewed by 5004

Abstract

Carbonic anhydrase inhibitors (CAIs), such as dorzolamide (DZA), are used as anti-glaucoma drugs to lower intraocular pressure, but it has been found that some of these drugs act as vasodilators of retinal arteries. The exact mechanism behind the vasodilatory effect is not yet clear. Here we have addressed the issue by using small vessel myography to examine the effect of CAIs of the sulfonamide and coumarin type on the wall tension in isolated segments of porcine retinal arteries. Vessels were pre-contracted by the prostaglandin analog U-46619, and CAIs with varying affinity for five different carbonic anhydrase (CA) isoenzymes found in human tissue tested. We found that all compounds tested cause a vasodilation of pre-contracted retinal arteries, but with varying efficacy, as indicated by the calculated mean EC₅₀ of each compound, ranging from 4.12 µM to 0.86 mM. All compounds had a lower mean EC₅₀ compared to DZA. The dilation induced by benzolamide (BZA) and DZA was additive, suggesting that they may act on separate mechanisms. No clear pattern in efficacy and affinity for CA isoenzymes could be discerned from the results, although Compound 5, with a low affinity for all isoenzymes except the human (h) CA isoform IV, had the greatest potency, with the lowest EC₅₀ and inducing the most rapid and profound dilation of the vessels. The results suggest that more than one isozyme of CA is involved in mediating its role in controlling vascular tone in retinal arteries, with a probable crucial role played by the membrane-bound isoform CA IV. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Figure 1

17 pages, 3394 KiB

Open AccessArticle

Investigation of the Prognostic Role of Carbonic Anhydrase 9 (CAIX) of the Cellular mRNA/Protein Level or Soluble CAIX Protein in Patients with Oral Squamous Cell Carcinoma

by Alexander W. Eckert, Susanne Horter, Daniel Bethmann, Johanna Kotrba, Tom Kaune, Swetlana Rot, Matthias Bache, Udo Bilkenroth, Waldemar Reich, Thomas Greither, Claudia Wickenhauser, Dirk Vordermark, Helge Taubert and Matthias Kappler

Int. J. Mol. Sci. 2019, 20(2), 375; https://doi.org/10.3390/ijms20020375 - 16 Jan 2019

Cited by 22 | Viewed by 4517

Abstract

Carbonic anhydrase 9 (CAIX) is an important protein that stabilizes the extracellular pH value and is transcriptionally regulated by hypoxia-inducible factor 1 (HIF1), but more stable than HIF1α. Here we show a comparative study that examines the prognostic value of CA9 mRNA, CAIX protein of tumor cells and secreted CAIX protein for oral squamous cell carcinoma (OSCC) patients. Tumor samples from 72 OSCC patients and 24 samples of normal tissue were analyzed for CA9 mRNA levels. A total of 158 OSCC samples were stained for CAIX by immunohistochemistry and 89 blood serum samples were analyzed by ELISA for soluble CAIX protein content. Survival analyses were performed by Kaplan–Meier and Cox’s regression analysis to estimate the prognostic effect of CA9/CAIX in OSCC patients. The CA9 mRNA and CAIX protein levels of tumor cells correlated with each other, but not with those of the secreted CAIX protein level of the blood of patients. ROC curves showed a significant (p < 0.001) higher mRNA-level of CA9 in OSCC samples than in adjacent normal tissue. Cox’s regression analysis revealed an increased risk (i) of death for patients with a high CA9 mRNA level (RR = 2.2; p = 0.02), (ii) of locoregional recurrence (RR = 3.2; p = 0.036) at higher CA9 mRNA levels and (iii) of death at high CAIX protein level in their tumors (RR = 1.7; p = 0.066) and especially for patients with advanced T4-tumors (RR = 2.0; p = 0.04). However, the secreted CAIX protein level was only as a trend associated with prognosis in OSCC (RR = 2.2; p = 0.066). CA9/CAIX is an independent prognostic factor for OSCC patients and therefore a potential therapeutic target. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Figure 1

11 pages, 1702 KiB

Open AccessArticle

Sulfonamide Inhibition Studies of a New β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica

by Silvia Bua, Susanna Haapanen, Marianne Kuuslahti, Seppo Parkkila and Claudiu T. Supuran

Int. J. Mol. Sci. 2018, 19(12), 3946; https://doi.org/10.3390/ijms19123946 - 8 Dec 2018

Cited by 10 | Viewed by 3621

Abstract

A newly described β-carbonic anhydrase (CA, EC 4.2.1.1) from the pathogenic protozoan Entamoeba histolytica, EhiCA, was recently shown to possess a significant catalytic activity for the physiologic CO₂ hydration reaction (k_cat of 6.7 × 10⁵ s⁻¹ and a k_cat/K_m of 8.9 × 10⁷ M⁻¹ s⁻¹). A panel of sulfonamides and one sulfamate, some of which are clinically used drugs, were investigated for their inhibitory properties against EhiCA. The best inhibitors detected in the study were 4-hydroxymethyl/ethyl-benzenesulfonamide (K_Is of 36–89 nM), whereas some sulfanilyl-sulfonamides showed activities in the range of 285–331 nM. Acetazolamide, methazolamide, ethoxzolamide, and dichlorophenamide were less effective inhibitors (K_Is of 509–845 nM) compared to other sulfonamides investigated here. As β-CAs are not present in vertebrates, the present study may be useful for detecting lead compounds for the design of more effective inhibitors with potential to develop anti-infectives with alternative mechanisms of action. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Graphical abstract

12 pages, 3752 KiB

Open AccessArticle

Comparison of the Anion Inhibition Profiles of the α-CA Isoforms (SpiCA1, SpiCA2 and SpiCA3) from the Scleractinian Coral Stylophora pistillata

by Sonia Del Prete, Silvia Bua, Didier Zoccola, Fatmah A.S. Alasmary, Zeid AlOthman, Linah S. Alqahtani, Nathalie Techer, Claudiu T. Supuran, Sylvie Tambutté and Clemente Capasso

Int. J. Mol. Sci. 2018, 19(7), 2128; https://doi.org/10.3390/ijms19072128 - 21 Jul 2018

Cited by 11 | Viewed by 4274

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes used by living organisms to accelerate the CO₂ hydration/dehydration reaction at rates dramatically high compared to the uncatalyzed reaction. These enzymes have different isoforms and homologues and can be found in the form of cytoplasmic, secreted or membrane-bound proteins. CAs play a role in numerous physiological processes including biomineralization and symbiosis, as is the case in reef-building corals. Previously, molecular and biochemical data have been obtained at the molecular level in the branching coral Stylophora pistillata for two coral isoforms which differ significantly in their catalytic activity and susceptibility to inhibition with anions and sulfonamides. More recently it has been determined that the genome of S. pistillata encodes for 16 CAs. Here, we cloned, expressed, purified and characterized a novel α-CA, named SpiCA3, which is cytoplasmic and ubiquitously expressed in all the cell layers including the calcifying cells. SpiCA3 is the most effective CA among the coral isoforms investigated and the most efficient catalyst known up to date in Metazoa. We also investigated the inhibition profiles of SpiCA3 and compared it with those obtained for the two other isoforms in the presence of inorganic anions and other small molecules known to interfere with metalloenzymes. These results suggest that S. pistillata has adapted its CA isoforms to achieve the physiological functions in different physicochemical microenvironments. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Graphical abstract

12 pages, 2553 KiB

Open AccessArticle

Development of a Fingerprint-Based Scoring Function for the Prediction of the Binding Mode of Carbonic Anhydrase II Inhibitors

by Giulio Poli, Vibhu Jha, Adriano Martinelli, Claudiu T. Supuran and Tiziano Tuccinardi

Int. J. Mol. Sci. 2018, 19(7), 1851; https://doi.org/10.3390/ijms19071851 - 23 Jun 2018

Cited by 11 | Viewed by 5045

Abstract

Carbonic anhydrase II (CAII) is a zinc-containing metalloenzyme whose aberrant activity is associated with various diseases such as glaucoma, osteoporosis, and different types of tumors; therefore, the development of CAII inhibitors, which can represent promising therapeutic agents for the treatment of these pathologies, is a current topic in medicinal chemistry. Molecular docking is a commonly used tool in structure-based drug design of enzyme inhibitors. However, there is still a need for improving docking reliability, especially in terms of scoring functions, since the complex pattern of energetic contributions driving ligand–protein binding cannot be properly described by mathematical functions only including approximated energetic terms. Here we report a novel CAII-specific fingerprint-based (IFP) scoring function developed according to the ligand–protein interactions detected in the CAII-inhibitor co-crystal structures of the most potent CAII ligands. Our IFP scoring function outperformed the ability of Autodock4 scoring function to identify native-like docking poses of CAII inhibitors and thus allowed a considerable improvement of docking reliability. Moreover, the ligand–protein interaction fingerprints showed a useful application in the binding mode analysis of structurally diverse CAII ligands. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Figure 1

12 pages, 1468 KiB

Open AccessArticle

The Crystal Structure of a hCA VII Variant Provides Insights into the Molecular Determinants Responsible for Its Catalytic Behavior

by Martina Buonanno, Anna Di Fiore, Emma Langella, Katia D’Ambrosio, Claudiu T. Supuran, Simona Maria Monti and Giuseppina De Simone

Int. J. Mol. Sci. 2018, 19(6), 1571; https://doi.org/10.3390/ijms19061571 - 24 May 2018

Cited by 24 | Viewed by 4109

Abstract

Although important progress has been achieved in understanding the catalytic mechanism of Carbonic Anhydrases, a detailed picture of all factors influencing the catalytic efficiency of the various human isoforms is still missing. In this paper we report a detailed structural study and theoretical pKa calculations on a hCA VII variant. The obtained data were compared with those already known for another thoroughly investigated cytosolic isoform, hCA II. Our structural studies show that in hCA VII the network of ordered water molecules, which connects the zinc bound solvent molecule to the proton shuttle His64, is altered compared to hCA II, causing a reduction of the catalytic efficiency. Theoretical calculations suggest that changes in solvent network are related to the difference in pKa of the proton shuttle in the two enzymes. The residue that plays a major role in determining the diverse pKa values of the proton shuttle is the one in position four, namely His for hCA II and Gly for hCA VII. This residue is located on the protein surface, outside of the active site cavity. These findings are in agreement with our previous studies that highlighted the importance of histidines on the protein surface of hCA II (among which His4) as crucial residues for the high catalytic efficiency of this isoform. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Figure 1

2297 KiB

Open AccessArticle

Low Levels of IgG Recognizing the α-1-Antitrypsin Peptide and Its Association with Taiwanese Women with Primary Sjögren’s Syndrome

by Yu-Sheng Chang, Chih-Hong Pan, Che-Chang Chang, Kai-Leun Tsai, Han-Wen Chou, Jin-Hua Chen, Sheng-Hong Lin, Yi-Ying Lu, Chih-Chun Tai, Yi-Fang Lin and Ching-Yu Lin

Int. J. Mol. Sci. 2017, 18(12), 2750; https://doi.org/10.3390/ijms18122750 - 18 Dec 2017

Cited by 3 | Viewed by 4011

Abstract

The aim of this study was to examine oxidative stress and low level of α-1-antitrypsin (A1AT) in primary Sjögren’s syndrome (pSS), and evaluate the associated autoreactivity against unmodified and their 4-hydroxy-2-nonenal (HNE)-modified peptides with pSS. Two differentially expressed proteins, α-1-acid glycoprotein 1 (A1AG1) and A1AT, exhibited 2-fold differences, and their HNE modifications were identified by depleted-albumin and immunoglobulin G (IgG) serum protein, in-solution digestion, in-gel digestion, and nano-liquid chromatography–tandem mass spectrometry (nano-LC-MS/MS) from pSS patients and age-matched healthy controls (HCs). Furthermore, levels of proteins, confirmation of HNE modifications, HNE-protein adducts and autoreactivity against unmodified and their HNE-modified peptides were further validated. Levels of the HNE-protein adduct and A1AG1 were significantly higher in pSS patients than HCs, but levels of A1AT were significantly lower in pSS patients compared to HCs. Only the HNE modification of A1AT was confirmed. Our study suggests that elevated HNE-protein adduct, oxidative stress, level (odds ratio (OR) 4.877, p = 0.003), lowered A1AT level (OR 3.910, p = 0.010) and a decreased level of anti-A1AT^50–63 IgG (OR 3.360, p = 0.010) showed an increased risk in pSS patients compared to HCs, respectively. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Figure 1

Review

Jump to: Research

22 pages, 1073 KiB

Open AccessReview

Discovery of Food-Derived Dipeptidyl Peptidase IV Inhibitory Peptides: A Review

by Rui Liu, Jianming Cheng and Hao Wu

Int. J. Mol. Sci. 2019, 20(3), 463; https://doi.org/10.3390/ijms20030463 - 22 Jan 2019

Cited by 126 | Viewed by 6874

Abstract

Diabetes is a chronic metabolic disorder which leads to high blood sugar levels over a prolonged period. Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and results from the body’s ineffective use of insulin. Over ten dipeptidyl peptidase IV (DPP-IV) inhibitory drugs have been developed and marketed around the world in the past decade. However, owing to the reported adverse effects of the synthetic DPP-IV inhibitors, attempts have been made to find DPP-IV inhibitors from natural sources. Food-derived components, such as protein hydrolysates (peptides), have been suggested as potential DPP-IV inhibitors which can help manage blood glucose levels. This review focuses on the methods of discovery of food-derived DPP-IV inhibitory peptides, including fractionation and purification approaches, in silico analysis methods, in vivo studies, and the bioavailability of these food-derived peptides. Moreover, food-derived DPP-IV inhibitory peptides discovered during this decade are listed and distributed in a 3D scatter plot graph based on their IC₅₀, molecular weight, and grand average of hydropathicity values, which can help us to understand the relationship between the features of the peptides and their activities. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

► Show Figures

Journal Menu

Journal Browser

Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (9 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI