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Advancements in Protease and Carbonic Anhydrase Inhibitors as Targeted Therapies in Infection and Disease

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

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 10998

Special Issue Editors

Prof. Dr. Kaye J. Williams

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Guest Editor
Faculty of Biology, Medicine and Health, School of Pharmacy and Optometry, University of Manchester, Manchester M13 9PL, UK
Dr. Roben Gieling

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Guest Editor
Faculty of Health and Life Sciences, Department of Applied Sciences, University of Northumbria, Newcastle Upon Tyne NE1 8ST, UK

Special Issue Information

Dear Colleagues,

Proteases are targeted clinically with selective inhibitors, and are mostly used as antiviral agents to treat HIV/AIDS and hepatitis C infections. The potential use of protease inhibitors to block the replication of human coronaviruses has also accelerated in the fight against Covid-19 worldwide. Carbonic anhydrases are expressed widely in cells and tissues, and broad-spectrum CA inhibitors like acetazolamide are widely used in the treatment of glaucoma, epilepsy and altitude sickness. The generation of CA isoform selective inhibitors enabled their potential wider use, most noticeably the CAIX/XII inhibitors in malignant neoplasms. The cellular response to external stimulus like hypoxia and low tissue oxygen is a common cause of the activation of proteases and carbonic anhydrases in response to ischemia, haemorrhage or neoplasms. Hypoxia causes the activation of the hypoxia-inducible factor 1 pathway via the stabilisation of the HIF-1 alpha subunit and the regulation of genes carrying the hypoxia-response element. The upregulation of CAIX/XII on neoplastic cells enhances the ability to maintain the acid–base balance and to induce cell migration, allowing them to survive the hypoxic conditions. Shedding of the extracellular catalytic domain of CAIX may potentially be a double-edged sword as an indicator of effective antitumour chemotherapy as well as acting as an autocrine/paracrine factor contributing to tumour progression and resistance.  

The present Special Issue of the International Journal of Molecular Sciences welcomes contributions dealing with all aspects connected to the chemistry, biochemistry, virology, pharmacology and toxicology of this important class of enzyme inhibitors.

Prof. Dr. Kaye J. Williams
Dr. Roben Gieling
Guest Editors

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Published Papers (3 papers)

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Research

10 pages, 2704 KiB  
Article
Improving the Laboratory Diagnosis of M-like Variants Related to Alpha1-Antitrypsin Deficiency
by Valentina Barzon, Stefania Ottaviani, Alice Maria Balderacchi, Alessandra Corino, Davide Piloni, Giulia Accordino, Manuela Coretti, Francesca Mariani, Angelo Guido Corsico and Ilaria Ferrarotti
Int. J. Mol. Sci. 2022, 23(17), 9859; https://doi.org/10.3390/ijms23179859 - 30 Aug 2022
Cited by 5 | Viewed by 2099
Abstract
Alpha1-antitrypsin (AAT) is a serine protease inhibitor that is encoded by the highly polymorphic SERPINA1 gene. Mutations in this gene can lead to AAT deficiency (AATD), which is associated with an increased risk of lung and/or liver disease. On the basis of electrophoretic [...] Read more.
Alpha1-antitrypsin (AAT) is a serine protease inhibitor that is encoded by the highly polymorphic SERPINA1 gene. Mutations in this gene can lead to AAT deficiency (AATD), which is associated with an increased risk of lung and/or liver disease. On the basis of electrophoretic migration, AAT variants are named with capital letters; M (medium) signifies the normal protein. Among pathological variants, the M-like ones represent a heterogeneous group of rare allelic variants that exhibit the same electrophoretic pattern as the M wild-type protein, which makes them difficult to detect with routine methods. In order to avoid their misdiagnosis, the present study defines and validates effective methods for the detection of two pathogenic M-like variants, Mwurzburg and Mwhitstable. Comparison of protein phenotypes using isoelectric focusing of samples that presented the Mwurzburg variant, as revealed by exons 5 sequencing, identified a particular electrophoretic pattern amenable to the Mwurzburg protein. The specific phenotyping pattern was retrospectively validated, thus enabling the detection of 16 patients with Mwurzburg variant among the subjects already tested but not sequenced according to our diagnostic algorithm. The Mwhitstable allele was detected by intron 4 sequencing of SERPINA1 gene. Mwurzburg and Mwhitstable are often misdiagnosed and the introduction of diagnostic improvements can help the clinical management, especially in patients with established lung disease without any other reported risk factors. Full article
(This article belongs to the Special Issue Advancements in Protease and Carbonic Anhydrase Inhibitors as Targeted Therapies in Infection and Disease)
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18 pages, 2477 KiB  
Article
Noscapine Acts as a Protease Inhibitor of In Vitro Elastase-Induced Collagen Deposition in Equine Endometrium
by Ana Amaral, Carina Fernandes, Anna Szóstek-Mioduchowska, Maria Rosa Rebordão, Dariusz Jan Skarzynski and Graça Ferreira-Dias
Int. J. Mol. Sci. 2021, 22(10), 5333; https://doi.org/10.3390/ijms22105333 - 19 May 2021
Cited by 5 | Viewed by 2661
Abstract
Endometrosis is a reproductive pathology that is responsible for mare infertility. Our recent studies have focused on the involvement of neutrophil extracellular traps enzymes, such as elastase (ELA), in the development of equine endometrosis. Noscapine (NOSC) is an alkaloid derived from poppy opium [...] Read more.
Endometrosis is a reproductive pathology that is responsible for mare infertility. Our recent studies have focused on the involvement of neutrophil extracellular traps enzymes, such as elastase (ELA), in the development of equine endometrosis. Noscapine (NOSC) is an alkaloid derived from poppy opium with anticough, antistroke, anticancer, and antifibrotic properties. The present work investigates the putative inhibitory in vitro effect of NOSC on collagen type I alpha 2 chain (COL1A2) mRNA and COL1 protein relative abundance induced by ELA in endometrial explants of mares in the follicular or mid-luteal phases at 24 or 48 h of treatment. The COL1A2 mRNA was evaluated by qPCR and COL1 protein relative abundance by Western blot. In equine endometrial explants, ELA increased COL 1 expression, while NOSC inhibited it at both estrous cycle phases and treatment times. These findings contribute to the future development of new endometrosis treatment approaches. Noscapine could be a drug capable of preventing collagen synthesis in mare’s endometrium and facilitate the therapeutic approach. Full article
(This article belongs to the Special Issue Advancements in Protease and Carbonic Anhydrase Inhibitors as Targeted Therapies in Infection and Disease)
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19 pages, 4196 KiB  
Article
Identification of Host Cellular Protein Substrates of SARS-COV-2 Main Protease
by Márió Miczi, Mária Golda, Balázs Kunkli, Tibor Nagy, József Tőzsér and János András Mótyán
Int. J. Mol. Sci. 2020, 21(24), 9523; https://doi.org/10.3390/ijms21249523 - 15 Dec 2020
Cited by 23 | Viewed by 5464
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-19 (COVID-19) being associated with severe pneumonia. Like with other viruses, the interaction of SARS-CoV-2 with host cell proteins is necessary for successful replication, and cleavage of cellular [...] Read more.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease-19 (COVID-19) being associated with severe pneumonia. Like with other viruses, the interaction of SARS-CoV-2 with host cell proteins is necessary for successful replication, and cleavage of cellular targets by the viral protease also may contribute to the pathogenesis, but knowledge about the human proteins that are processed by the main protease (3CLpro) of SARS-CoV-2 is still limited. We tested the prediction potentials of two different in silico methods for the identification of SARS-CoV-2 3CLpro cleavage sites in human proteins. Short stretches of homologous host-pathogen protein sequences (SSHHPS) that are present in SARS-CoV-2 polyprotein and human proteins were identified using BLAST analysis, and the NetCorona 1.0 webserver was used to successfully predict cleavage sites, although this method was primarily developed for SARS-CoV. Human C-terminal-binding protein 1 (CTBP1) was found to be cleaved in vitro by SARS-CoV-2 3CLpro, the existence of the cleavage site was proved experimentally by using a His6-MBP-mEYFP recombinant substrate containing the predicted target sequence. Our results highlight both potentials and limitations of the tested algorithms. The identification of candidate host substrates of 3CLpro may help better develop an understanding of the molecular mechanisms behind the replication and pathogenesis of SARS-CoV-2. Full article
(This article belongs to the Special Issue Advancements in Protease and Carbonic Anhydrase Inhibitors as Targeted Therapies in Infection and Disease)
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