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Therapeutic Targeting of the Proteolytic Enzymes
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Therapeutic Targeting of the Proteolytic Enzymes

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 (30 April 2022) | Viewed by 25630

Special Issue Editors

Dr. Anna Kwiatkowska

E-Mail Website
Guest Editor
Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, Canada
Interests: peptides and peptidomimetics; proteolytic enzymes; structure-based drug design; prostate cancer; infectious diseases
Dr. Frédéric Couture

E-Mail Website
Guest Editor
1. Pharmaceutical Sciences Department, TransBIOTech, Lévis, QC G6V 6Z3, Canada
2. Institute of Nutrition and Functional Foods, Laval University, Quebec, QC G1V 0A6, Canada
3. Centre de Recherche du Centre Intégré de Santé et de Services Sociaux de Chaudière-Appalaches, Lévis, QC G6V 3Z1, Canada
Interests: pharmacology (efficacy studies, PK-PD relationship, toxicology); oncology (tumor model, drug development); molecular biology (CRISPR, assay development); enzymology of proteolytic enzymes (proprotein convertases, inhibitor development, target engagement)

Special Issue Information

Dear Colleagues,

Proteases are key regulators of the protein function in virtually all biological pathways and represent one of the most abundant classes of enzymes. In the past, they have been considered as a cell's garbage disposals that degrade proteins to maintain general homeostasis. However, over the last few decades, this view has changed substantially with the increasing demonstrations that proteolytic enzymes act as signaling molecules and regulate critical cellular processes, including cell division, metabolism, and death, to name a few. The proteolytic cleavage (i.e., proteolysis) occurring in the intra-, peri- and extracellular environment is tightly regulated and represents a dynamic mean to transduce signals in auto- and paracrine ways. Dysregulation of this process underlies many diseases and pathological conditions such as cancer, inflammation, cardiovascular and neurodegenerative disorders. In addition, proteolysis by host proteases is an essential step of viral/bacterial infection determining its pathogenesis. Therefore, it is not surprising that proteases have become important therapeutic targets.

The interest in developing protease inhibitors has been growing constantly and has already led to numerous drugs on the market as well as promising candidates in the pipeline. However, a large number of therapeutically relevant proteases remains unexplored. Many of them lack the identification of the specific substrates as well as the signaling pathways that are affected by their activity. Therefore, a key step to obtain drugs with full pharmacological potential is a better understanding of proteases' mechanism of action in pathological conditions combined with a rational design of the therapeutic strategies targeting these enzymes.

This Special Issue is dedicated to all original research articles and reviews, exploring the therapeutic potential of proteases, with focus on the validation of targets, and the development of novel therapeutic strategies or advances in currently existing ones, with accent on pharmacological and molecular studies. Topics include but are not limited to:

  • Identification and validation of protease targets;
  • Development of strategies to monitor the activity of proteases;
  • New strategies to develop inhibitors.

Dr. Anna Kwiatkowska
Dr. Frédéric Couture
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.

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

  • proteases
  • inhibitors
  • target identification
  • screening
  • drug discovery
  • activity-based probes
  • target delivery
  • cancer
  • viral infections
  • inflammation

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 197 KiB  
Editorial
Therapeutic Targeting of the Proteolytic Enzymes
by Frédéric Couture
Int. J. Mol. Sci. 2023, 24(1), 521; https://doi.org/10.3390/ijms24010521 - 28 Dec 2022
Viewed by 1010
Abstract
The processes regulating the generation of proteins from the early translation events to the final biologically active products are complex and tightly controlled [...] Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)

Research

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13 pages, 2572 KiB  
Article
Alpha 1 Antitrypsin Regulates Trophoblast Syncytialization and Inflammatory Factor Expression
by Kanoko Yoshida, Aruto Yano, Kazuya Kusama, Gen Ishikawa and Kazuhiro Tamura
Int. J. Mol. Sci. 2022, 23(4), 1955; https://doi.org/10.3390/ijms23041955 - 10 Feb 2022
Cited by 4 | Viewed by 1797
Abstract
The serine protease inhibitor alpha1-antitrypsin (A1AT) may possess protective functions of impaired organs in a manner independent of its protease inhibitor activity. A1AT expression has been shown to fluctuate in patients with pregnancy-induced hypertension, which suggests that A1AT may play a role in [...] Read more.
The serine protease inhibitor alpha1-antitrypsin (A1AT) may possess protective functions of impaired organs in a manner independent of its protease inhibitor activity. A1AT expression has been shown to fluctuate in patients with pregnancy-induced hypertension, which suggests that A1AT may play a role in the syncytialization of villous trophoblasts. A1AT expression was knocked down in primary trophoblasts. RNA was extracted from these cells and subjected to RNA-sequencing analysis to determine the levels of expression of markers of syncytialization and inflammation. In addition, A1AT protein was localized in trophoblastic cells in placental tissues. Knockdown of A1AT upregulated the expression of FOSL1 and markers of syncytialization, as well as cell fusion, whereas overexpression of A1AT had the opposite effects. FOSL1 overexpression stimulated syncytialization, similar to the effects of A1AT knock down. Inhibitors of p38MAPK and JNK reduce the expression of inflammatory factors, whereas a p38MAPK inhibitor suppressed FOSL1 expression. Collectively, these findings indicated A1AT may negatively regulate inflammatory responses by controlling the activation of p38MAPK and JNK, and that p38MAPK mediates trophoblast syncytialization by altering FOSL1 expression. Therefore, a dysfunction in A1AT could be responsible for abnormal placental formation and pregnancy-associated disorders. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)
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18 pages, 2374 KiB  
Article
Generation of Lasso Peptide-Based ClpP Binders
by Imran T. Malik, Julian D. Hegemann and Heike Brötz-Oesterhelt
Int. J. Mol. Sci. 2022, 23(1), 465; https://doi.org/10.3390/ijms23010465 - 31 Dec 2021
Cited by 3 | Viewed by 3291
Abstract
The Clp protease system fulfills a plethora of important functions in bacteria. It consists of a tetradecameric ClpP barrel holding the proteolytic centers and two hexameric Clp-ATPase rings, which recognize, unfold, and then feed substrate proteins into the ClpP barrel for proteolytic degradation. [...] Read more.
The Clp protease system fulfills a plethora of important functions in bacteria. It consists of a tetradecameric ClpP barrel holding the proteolytic centers and two hexameric Clp-ATPase rings, which recognize, unfold, and then feed substrate proteins into the ClpP barrel for proteolytic degradation. Flexible loops carrying conserved tripeptide motifs protrude from the Clp-ATPases and bind into hydrophobic pockets (H-pockets) on ClpP. Here, we set out to engineer microcin J25 (MccJ25), a ribosomally synthesized and post-translationally modified peptide (RiPP) of the lasso peptide subfamily, by introducing the conserved tripeptide motifs into the lasso peptide loop region to mimic the Clp-ATPase loops. We studied the capacity of the resulting lasso peptide variants to bind to ClpP and affect its activity. From the nine variants generated, one in particular (12IGF) was able to activate ClpP from Staphylococcus aureus and Bacillus subtilis. While 12IGF conferred stability to ClpP tetradecamers and stimulated peptide degradation, it did not trigger unregulated protein degradation, in contrast to the H-pocket-binding acyldepsipeptide antibiotics (ADEPs). Interestingly, synergistic interactions between 12IGF and ADEP were observed. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)
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13 pages, 2134 KiB  
Article
Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice
by Ilaria Coppola, Bas Brouwers, Sandra Meulemans, Bruno Ramos-Molina and John W. M. Creemers
Int. J. Mol. Sci. 2021, 22(12), 6344; https://doi.org/10.3390/ijms22126344 - 14 Jun 2021
Cited by 7 | Viewed by 3245
Abstract
The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β [...] Read more.
The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific Furin knockout (βFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in βFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)
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Review

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12 pages, 1138 KiB  
Review
The Path to Therapeutic Furin Inhibitors: From Yeast Pheromones to SARS-CoV-2
by Gary Thomas, Frédéric Couture and Anna Kwiatkowska
Int. J. Mol. Sci. 2022, 23(7), 3435; https://doi.org/10.3390/ijms23073435 - 22 Mar 2022
Cited by 7 | Viewed by 3108
Abstract
The spurious acquisition and optimization of a furin cleavage site in the SARS-CoV-2 spike protein is associated with increased viral transmission and disease, and has generated intense interest in the development and application of therapeutic furin inhibitors to thwart the COVID-19 pandemic. This [...] Read more.
The spurious acquisition and optimization of a furin cleavage site in the SARS-CoV-2 spike protein is associated with increased viral transmission and disease, and has generated intense interest in the development and application of therapeutic furin inhibitors to thwart the COVID-19 pandemic. This review summarizes the seminal studies that informed current efforts to inhibit furin. These include the convergent efforts of endocrinologists, virologists, and yeast geneticists that, together, culminated in the discovery of furin. We describe the pioneering biochemical studies which led to the first furin inhibitors that were able to block the disease pathways which are broadly critical for pathogen virulence, tumor invasiveness, and atherosclerosis. We then summarize how these studies subsequently informed current strategies leading to the development of small-molecule furin inhibitors as potential therapies to combat SARS-CoV-2 and other diseases that rely on furin for their pathogenicity and progression. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)
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27 pages, 13617 KiB  
Review
The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment
by Lukas Wettstein, Frank Kirchhoff and Jan Münch
Int. J. Mol. Sci. 2022, 23(3), 1351; https://doi.org/10.3390/ijms23031351 - 25 Jan 2022
Cited by 34 | Viewed by 5787
Abstract
TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a [...] Read more.
TMPRSS2 is a type II transmembrane protease with broad expression in epithelial cells of the respiratory and gastrointestinal tract, the prostate, and other organs. Although the physiological role of TMPRSS2 remains largely elusive, several endogenous substrates have been identified. TMPRSS2 serves as a major cofactor in SARS-CoV-2 entry, and primes glycoproteins of other respiratory viruses as well. Consequently, inhibiting TMPRSS2 activity is a promising strategy to block viral infection. In this review, we provide an overview of the role of TMPRSS2 in the entry processes of different respiratory viruses. We then review the different classes of TMPRSS2 inhibitors and their clinical development, with a focus on COVID-19 treatment. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)
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21 pages, 3566 KiB  
Review
Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm
by Shinya Yamada and Hidesaku Asakura
Int. J. Mol. Sci. 2022, 23(3), 1296; https://doi.org/10.3390/ijms23031296 - 24 Jan 2022
Cited by 13 | Viewed by 6112
Abstract
Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. [...] Read more.
Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α2 plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance. Full article
(This article belongs to the Special Issue Therapeutic Targeting of the Proteolytic Enzymes)
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