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Proteases—From Basic Structure to Function to Drug Design as Targeted...
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Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 24426

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Hang Fai (Henry) Kwok

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Guest Editor
1. Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR 999078, China
2. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR 999078, China
Interests: novel therapeutic antibodies development; venom-based peptide & natural biomolecule prototype drugs development; cancer biomarkers & immunotherapy markers discovery for prognostic and therapeutic validation
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Christopher Shaw

E-Mail Website
Guest Editor
School of Pharmacy, Queen's University Belfast, Belfast BT7 1NN, UK
Interests: natural peptide; mass spectrometry; antibiotic resistance; structure–activity relationship; membrane selectivity
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Brian Walker

E-Mail Website
Guest Editor
School of Pharmacy, Queen's University Belfast, University Road, Belfast, BT7 1NN, Northern Ireland, UK
Interests: development and application of novel inhibitors for the identification and validation of protease targets of biomedical and pharmaceutical importance

Special Issue Information

Dear Colleagues,

In the two last decades, proteases have constituted one of the primary and important targets in drug discovery. The U.S. FDA has approved more than 12 protease therapies in the last 10 years, and a number of next generation or completely new proteases are under clinical development. Protease inhibition strategy is one of the fastest expanding classes of drugs that show considerable promise. This Special Issue will focus on recent advances in protease inhibitors discovery and development, covering the synthesis of protease inhibitors, the design of new chemical entities acting as inhibitors of special/particular types of proteases, and their mode of actions (such as anti-viral, proteasome, calpain, metalloprotease, etc.). In addition, the new applications of these interesting compounds/biomolecules and their limitations will be discussed and described.

This Special Issue welcomes the submission of original research, short communications, and review manuscripts focusing on proteases for the diagnosis, therapy, and theranostics of a wide range of diseases, especially in targeted therapy approaches for cancer treatment. We welcome specific protease drug design and development technologies employed in their identification and targeting, helping us to provide a realistic overview of this exciting and interdisciplinary field of biomedical research.

Prof. Dr. Hang Fai (Henry) Kwok
Prof. Dr. Christopher Shaw
Prof. Dr. Brian Walker
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. Biology 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

  • protease inhibitor
  • targeted therapy
  • drug design and development
  • oncology
  • precision medicine

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Published Papers (6 papers)

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Editorial

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2 pages, 193 KiB  
Editorial
Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy
by Hang Fai Kwok, Brian Walker and Chris Shaw
Biology 2022, 11(11), 1680; https://doi.org/10.3390/biology11111680 - 21 Nov 2022
Cited by 1 | Viewed by 1361
Abstract
In the last two decades, proteases have become a primary and vital target in drug discovery [...] Full article
(This article belongs to the Special Issue Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy)

Research

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16 pages, 2328 KiB  
Article
Evolutionary Analysis of Cystatins of Early-Emerging Metazoans Reveals a Novel Subtype in Parasitic Cnidarians
by Pavla Bartošová-Sojková, Jiří Kyslík, Gema Alama-Bermejo, Ashlie Hartigan, Stephen D. Atkinson, Jerri L. Bartholomew, Amparo Picard-Sánchez, Oswaldo Palenzuela, Marc Nicolas Faber, Jason W. Holland and Astrid S. Holzer
Biology 2021, 10(2), 110; https://doi.org/10.3390/biology10020110 - 3 Feb 2021
Cited by 7 | Viewed by 4270
Abstract
The evolutionary aspects of cystatins are greatly underexplored in early-emerging metazoans. Thus, we surveyed the gene organization, protein architecture, and phylogeny of cystatin homologues mined from 110 genomes and the transcriptomes of 58 basal metazoan species, encompassing free-living and parasite taxa of Porifera, [...] Read more.
The evolutionary aspects of cystatins are greatly underexplored in early-emerging metazoans. Thus, we surveyed the gene organization, protein architecture, and phylogeny of cystatin homologues mined from 110 genomes and the transcriptomes of 58 basal metazoan species, encompassing free-living and parasite taxa of Porifera, Placozoa, Cnidaria (including Myxozoa), and Ctenophora. We found that the cystatin gene repertoire significantly differs among phyla, with stefins present in most of the investigated lineages but with type 2 cystatins missing in several basal metazoan groups. Similar to liver and intestinal flukes, myxozoan parasites possess atypical stefins with chimeric structure that combine motifs of classical stefins and type 2 cystatins. Other early metazoan taxa regardless of lifestyle have only the classical representation of cystatins and lack multi-domain ones. Our comprehensive phylogenetic analyses revealed that stefins and type 2 cystatins clustered into taxonomically defined clades with multiple independent paralogous groups, which probably arose due to gene duplications. The stefin clade split between the subclades of classical stefins and the atypical stefins of myxozoans and flukes. Atypical stefins represent key evolutionary innovations of the two parasite groups for which their origin might have been linked with ancestral gene chimerization, obligate parasitism, life cycle complexity, genome reduction, and host immunity. Full article
(This article belongs to the Special Issue Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy)
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15 pages, 4802 KiB  
Article
Ranacyclin-NF, a Novel Bowman–Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, Pelophylax nigromaculatus
by Tao Wang, Yangyang Jiang, Xiaoling Chen, Lei Wang, Chengbang Ma, Xinping Xi, Yingqi Zhang, Tianbao Chen, Chris Shaw and Mei Zhou
Biology 2020, 9(7), 149; https://doi.org/10.3390/biology9070149 - 2 Jul 2020
Cited by 8 | Viewed by 3482
Abstract
Serine protease inhibitors are found in plants, animals and microorganisms, where they play important roles in many physiological and pathological processes. Inhibitor scaffolds based on natural proteins and peptides have gradually become the focus of current research as they tend to bind to [...] Read more.
Serine protease inhibitors are found in plants, animals and microorganisms, where they play important roles in many physiological and pathological processes. Inhibitor scaffolds based on natural proteins and peptides have gradually become the focus of current research as they tend to bind to their targets with greater specificity than small molecules. In this report, a novel Bowman–Birk type inhibitor, named ranacyclin-NF (RNF), is described and was identified in the skin secretion of the East Asian frog, Pelophylax nigromaculatus. A synthetic replicate of the peptide was subjected to a series of functional assays. It displayed trypsin inhibitory activity with an inhibitory constant, Ki, of 447 nM and had negligible direct cytotoxicity. No observable direct antimicrobial activity was found but RNF improved the therapeutic potency of Gentamicin against Methicillin-resistant Staphylococcus aureus (MRSA). RNF shared significant sequence similarity to previously reported and related inhibitors from Odorrana grahami (ORB) and Rana esculenta (ranacyclin-T), both of which were found to be multi-functional. Two analogues of RNF, named ranacyclin-NF1 (RNF1) and ranacyclin-NF3L (RNF3L), were designed based on some features of ORB and ranacyclin-T to study structure–activity relationships. Structure–activity studies demonstrated that residues outside of the trypsin inhibitory loop (TIL) may be related to the efficacy of trypsin inhibitory activity. Full article
(This article belongs to the Special Issue Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy)
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Review

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23 pages, 3524 KiB  
Review
Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs
by Jaana Künnapuu, Honey Bokharaie and Michael Jeltsch
Biology 2021, 10(2), 167; https://doi.org/10.3390/biology10020167 - 23 Feb 2021
Cited by 32 | Viewed by 6307
Abstract
Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph­angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal [...] Read more.
Specific proteolytic cleavages turn on, modify, or turn off the activity of vascular endothelial growth factors (VEGFs). Proteolysis is most prominent among the lymph­angiogenic VEGF-C and VEGF-D, which are synthesized as precursors that need to undergo enzymatic removal of their C- and N-terminal propeptides before they can activate their receptors. At least five different proteases mediate the activating cleavage of VEGF-C: plasmin, ADAMTS3, prostate-specific antigen, cathepsin D, and thrombin. All of these proteases except for ADAMTS3 can also activate VEGF-D. Processing by different proteases results in distinct forms of the “mature” growth factors, which differ in affinity and receptor activation potential. The “default” VEGF-C-activating enzyme ADAMTS3 does not activate VEGF-D, and therefore, VEGF-C and VEGF-D do function in different contexts. VEGF-C itself is also regulated in different contexts by distinct proteases. During embryonic development, ADAMTS3 activates VEGF-C. The other activating proteases are likely important for non-developmental lymphangiogenesis during, e.g., tissue regeneration, inflammation, immune response, and pathological tumor-associated lymphangiogenesis. The better we understand these events at the molecular level, the greater our chances of developing successful therapies targeting VEGF-C and VEGF-D for diseases involving the lymphatics such as lymphedema or cancer. Full article
(This article belongs to the Special Issue Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy)
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20 pages, 1508 KiB  
Review
Unravelling the Network of Nuclear Matrix Metalloproteinases for Targeted Drug Design
by Anastasia S. Frolova, Anastasiia I. Petushkova, Vladimir A. Makarov, Surinder M. Soond and Andrey A. Zamyatnin, Jr.
Biology 2020, 9(12), 480; https://doi.org/10.3390/biology9120480 - 19 Dec 2020
Cited by 7 | Viewed by 3467
Abstract
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are responsible for the degradation of a wide range of extracellular matrix proteins, which are involved in many cellular processes to ensure the normal development of tissues and organs. Overexpression of MMPs has been observed to [...] Read more.
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are responsible for the degradation of a wide range of extracellular matrix proteins, which are involved in many cellular processes to ensure the normal development of tissues and organs. Overexpression of MMPs has been observed to facilitate cellular growth, migration, and metastasis of tumor cells during cancer progression. A growing number of these proteins are being found to exist in the nuclei of both healthy and tumor cells, thus highlighting their localization as having a genuine purpose in cellular homeostasis. The mechanism underlying nuclear transport and the effects of MMP nuclear translocation have not yet been fully elucidated. To date, nuclear MMPs appear to have a unique impact on cellular apoptosis and gene regulation, which can have effects on immune response and tumor progression, and thus present themselves as potential therapeutic targets in certain types of cancer or disease. Herein, we highlight and evaluate what progress has been made in this area of research, which clearly has some value as a specific and unique way of targeting the activity of nuclear matrix metalloproteinases within various cell types. Full article
(This article belongs to the Special Issue Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy)
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21 pages, 550 KiB  
Review
Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?
by Etienne J. Slapak, JanWillem Duitman, Cansu Tekin, Maarten F. Bijlsma and C. Arnold Spek
Biology 2020, 9(4), 80; https://doi.org/10.3390/biology9040080 - 18 Apr 2020
Cited by 57 | Viewed by 4323
Abstract
Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been [...] Read more.
Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression. Based upon this notion, changes in matrix metalloprotease expression levels are often considered surrogate markers for pancreatic cancer progression and/or treatment response. Indeed, reduced matrix metalloprotease levels upon treatment (either pharmacological or due to genetic ablation) are considered as proof of the anti-tumorigenic potential of the mediator under study. In the current review, we aim to establish whether matrix metalloproteases indeed drive pancreatic cancer progression and whether decreased matrix metalloprotease levels in experimental settings are therefore indicative of treatment response. After a systematic review of the studies focusing on matrix metalloproteases in pancreatic cancer, we conclude that the available literature is not as convincing as expected and that, although individual matrix metalloproteases may contribute to pancreatic cancer growth and metastasis, this does not support the generalized notion that matrix metalloproteases drive pancreatic ductal adenocarcinoma progression. Full article
(This article belongs to the Special Issue Proteases—From Basic Structure to Function to Drug Design as Targeted Therapy)
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