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The Biology and Therapeutic Potential of Metalloproteases
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The Biology and Therapeutic Potential of Metalloproteases

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

Deadline for manuscript submissions: 31 August 2024 | Viewed by 5702

Special Issue Editors

Dr. Efstratios Stratikos

E-Mail Website
Guest Editor
Department of Chemistry, National and Kapodistrian University of Athens, 15784 Zografou, Greece
Interests: aminopeptidases; enzymes; antigen presentation; adaptive immunity; cancer; inflammation; inhibitors; drug-design
Special Issues, Collections and Topics in MDPI journals
Dr. Dimitris Georgiadis

E-Mail Website
Guest Editor
Department of Chemistry, Laboratory of Organic Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Zografou, 15784 Athens, Greece
Interests: organic chemistry; medicinal chemistry; organophosphorus chemistry

Special Issue Information

Dear Colleagues,

We are thrilled to announce a Special Issue dedicated to the multifaceted realm of metallopeptidases. Metallopeptidases, a diverse family of enzymes containing metal ions in their active sites, play pivotal roles in a wide array of biological processes, including proteolysis, cellular signalling, the immune response, and the regulation of various physiological pathways. This Special Issue serves as a platform for researchers, scientists, and clinicians to delve deep into the captivating world of metallopeptidases.

Key focus areas of this Special Issue will include structural insights, mechanisms of function, biological roles, and pharmacology. This Special Issue aims to summarize all recent research achievements in the field of metalloproteases encouraging researchers to share their latest findings, methodologies, and insights. We invite contributions from experts in the field, spanning from fundamental research to translational applications, with the goal of advancing our understanding of these critical enzymes and their contributions to biology and medicine. 

Dr. Efstratios Stratikos
Dr. Dimitris Georgiadis
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

  • metalloproteases
  • enzymes
  • inhibitors
  • mechanisms
  • structure
  • drug targets
  • probes
  • proteolysis
  • disease mechanisms
  • metal

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Published Papers (5 papers)

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22 pages, 3302 KiB  
Article
Proteomic Analysis of Human Macrophages Overexpressing Angiotensin-Converting Enzyme
by Delia Oosthuizen, Tariq A. Ganief, Kenneth E. Bernstein and Edward D. Sturrock
Int. J. Mol. Sci. 2024, 25(13), 7055; https://doi.org/10.3390/ijms25137055 - 27 Jun 2024
Viewed by 561
Abstract
Angiotensin converting enzyme (ACE) exerts strong modulation of myeloid cell function independently of its cardiovascular arm. The success of the ACE-overexpressing murine macrophage model, ACE 10/10, in treating microbial infections and cancer opens a new avenue into whether ACE overexpression in human macrophages [...] Read more.
Angiotensin converting enzyme (ACE) exerts strong modulation of myeloid cell function independently of its cardiovascular arm. The success of the ACE-overexpressing murine macrophage model, ACE 10/10, in treating microbial infections and cancer opens a new avenue into whether ACE overexpression in human macrophages shares these benefits. Additionally, as ACE inhibitors are a widely used antihypertensive medication, their impact on ACE expressing immune cells is of interest and currently understudied. In the present study, we utilized mass spectrometry to characterize and assess global proteomic changes in an ACE-overexpressing human THP-1 cell line. Additionally, proteomic changes and cellular uptake following treatment with an ACE C-domain selective inhibitor, lisinopril–tryptophan, were also assessed. ACE activity was significantly reduced following inhibitor treatment, despite limited uptake within the cell, and both RNA processing and immune pathways were significantly dysregulated with treatment. Also present were upregulated energy and TCA cycle proteins and dysregulated cytokine and interleukin signaling proteins with ACE overexpression. A novel, functionally enriched immune pathway that appeared both with ACE overexpression and inhibitor treatment was neutrophil degranulation. ACE overexpression within human macrophages showed similarities with ACE 10/10 murine macrophages, paving the way for mechanistic studies aimed at understanding the altered immune function. Full article
(This article belongs to the Special Issue The Biology and Therapeutic Potential of Metalloproteases)
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19 pages, 3346 KiB  
Article
Evaluation of the Inhibitory Potential of Synthetic Peptides Homologous to CDR3 Regions of a Monoclonal Antibody against Bothropic Venom Serine Proteases
by Lucas Yuri Saladini, Marcos Jorge Magalhães-Junior, Cristiane Castilho Fernandes da Silva, Priscila Gonçalves Coutinho Oliveira, Roberto Tadashi Kodama, Lais Gomes, Milton Yutaka Nishiyama-Jr, Patrick Jack Spencer, Wilmar Dias da Silva and Fernanda Calheta Vieira Portaro
Int. J. Mol. Sci. 2024, 25(10), 5181; https://doi.org/10.3390/ijms25105181 - 9 May 2024
Viewed by 917
Abstract
Snakebite accidents, neglected tropical diseases per the WHO, pose a significant public health threat due to their severity and frequency. Envenomation by Bothrops genus snakes leads to severe manifestations due to proteolytic enzymes. While the antibothropic serum produced by the Butantan Institute saves [...] Read more.
Snakebite accidents, neglected tropical diseases per the WHO, pose a significant public health threat due to their severity and frequency. Envenomation by Bothrops genus snakes leads to severe manifestations due to proteolytic enzymes. While the antibothropic serum produced by the Butantan Institute saves lives, its efficacy is limited as it fails to neutralize certain serine proteases. Hence, developing new-generation antivenoms, like monoclonal antibodies, is crucial. This study aimed to explore the inhibitory potential of synthetic peptides homologous to the CDR3 regions of a monoclonal antibody targeting a snake venom thrombin-like enzyme (SVTLE) from B. atrox venom. Five synthetic peptides were studied, all stable against hydrolysis by venoms and serine proteases. Impressively, four peptides demonstrated uncompetitive SVTLE inhibition, with Ki values ranging from 10−6 to 10−7 M. These findings underscore the potential of short peptides homologous to CDR3 regions in blocking snake venom toxins, suggesting their promise as the basis for new-generation antivenoms. Thus, this study offers potential advancements in combatting snakebites, addressing a critical public health challenge in tropical and subtropical regions. Full article
(This article belongs to the Special Issue The Biology and Therapeutic Potential of Metalloproteases)
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18 pages, 2290 KiB  
Article
The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds
by Johan Gising, Saman Honarnejad, Maaike Bras, Gemma L. Baillie, Stuart P. McElroy, Philip S. Jones, Angus Morrison, Julia Beveridge, Mathias Hallberg and Mats Larhed
Int. J. Mol. Sci. 2024, 25(7), 4084; https://doi.org/10.3390/ijms25074084 - 6 Apr 2024
Viewed by 1416
Abstract
With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound [...] Read more.
With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration. Full article
(This article belongs to the Special Issue The Biology and Therapeutic Potential of Metalloproteases)
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30 pages, 4889 KiB  
Article
Inhibition of Insulin-Regulated Aminopeptidase by Imidazo [1,5-α]pyridines—Synthesis and Evaluation
by Karin Engen, Thomas Lundbäck, Anubha Yadav, Sharathna Puthiyaparambath, Ulrika Rosenström, Johan Gising, Annika Jenmalm-Jensen, Mathias Hallberg and Mats Larhed
Int. J. Mol. Sci. 2024, 25(5), 2516; https://doi.org/10.3390/ijms25052516 - 21 Feb 2024
Cited by 1 | Viewed by 1019
Abstract
Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on [...] Read more.
Inhibition of insulin-regulated aminopeptidase (IRAP) has been shown to improve cognitive functions in several animal models. Recently, we performed a screening campaign of approximately 10,000 compounds, identifying novel small-molecule-based compounds acting as inhibitors of the enzymatic activity of IRAP. Here we report on the chemical synthesis, structure-activity relationships (SAR) and initial characterization of physicochemical properties of a series of 48 imidazo [1,5-α]pyridine-based inhibitors, including delineation of their mode of action as non-competitive inhibitors with a small L-leucine-based IRAP substrate. The best compound displays an IC50 value of 1.0 µM. We elucidate the importance of two chiral sites in these molecules and find they have little impact on the compound’s metabolic stability or physicochemical properties. The carbonyl group of a central urea moiety was initially believed to mimic substrate binding to a catalytically important Zn2+ ion in the active site, although the plausibility of this binding hypothesis is challenged by observation of excellent selectivity versus the closely related aminopeptidase N (APN). Taken together with the non-competitive inhibition pattern, we also consider an alternative model of allosteric binding. Full article
(This article belongs to the Special Issue The Biology and Therapeutic Potential of Metalloproteases)
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13 pages, 4484 KiB  
Article
Involvement of PAR-2 in the Induction of Cell-Specific Matrix Metalloproteinase-2 by Activated Protein C in Cutaneous Wound Healing
by Sohel M. Julovi, Kelly McKelvey, Nikita Minhas, Yee-Ka Agnes Chan, Meilang Xue and Christopher J. Jackson
Int. J. Mol. Sci. 2024, 25(1), 370; https://doi.org/10.3390/ijms25010370 - 27 Dec 2023
Cited by 2 | Viewed by 1125
Abstract
We previously reported that human keratinocytes express protease-activated receptor (PAR)-2 and play an important role in activated protein C (APC)-induced cutaneous wound healing. This study investigated the involvement of PAR-2 in the production of gelatinolytic matrix metalloproteinases (MMP)-2 and -9 by APC during [...] Read more.
We previously reported that human keratinocytes express protease-activated receptor (PAR)-2 and play an important role in activated protein C (APC)-induced cutaneous wound healing. This study investigated the involvement of PAR-2 in the production of gelatinolytic matrix metalloproteinases (MMP)-2 and -9 by APC during cutaneous wound healing. Full-thickness excisional wounds were made on the dorsum of male C57BL/6 mice. Wounds were treated with APC on days 1, 2, and 3 post-wounding. Cultured neonatal foreskin keratinocytes were treated with APC with or without intact PAR-2 signalling to examine the effects on MMP-2 and MMP-9 production. Murine dermal fibroblasts from PAR-2 knock-out (KO) mice were also assessed. MMP-2 and -9 were measured via gelatin zymography, fluorometric assay, and immunohistochemistry. APC accelerated wound healing in WT mice, but had a negligible effect in PAR-2 KO mice. APC-stimulated murine cutaneous wound healing was associated with the differential and temporal production of MMP-2 and MMP-9, with the latter peaking on day 1 and the former on day 6. Inhibition of PAR-2 in human keratinocytes reduced APC-induced MMP-2 activity by 25~50%, but had little effect on MMP-9. Similarly, APC-induced MMP-2 activation was reduced by 40% in cultured dermal fibroblasts derived from PAR-2 KO mice. This study shows for the first time that PAR-2 is essential for APC-induced MMP-2 production. Considering the important role of MMP-2 in wound healing, this work helps explain the underlying mechanisms of action of APC to promote wound healing through PAR-2. Full article
(This article belongs to the Special Issue The Biology and Therapeutic Potential of Metalloproteases)
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