Inhibitory Antibodies Designed for Matrix Metalloproteinase Modulation

Fischer, Thomas; Riedl, Rainer

doi:10.3390/molecules24122265

Cited by 43 publications

(32 citation statements)

References 114 publications

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“…With this profile, inhibitor 50 offers potential in polypharmacology approaches through the simultaneous inhibition of two or more biological targets to tackle one disease. In a similar approach, the group developed a dual inhibitor for the target enzymes MMP‐7 and ‐13 . Polypharmacology represents an increasingly recognized strategy for the treatment of complex diseases, such as cancer or CNS diseases …”

Section: Mmp Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug‐discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small‐molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X‐ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure‐based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.

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Section: Mmp Inhibitorsmentioning

confidence: 99%

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Fischer

Senn

Riedl

2019

Chemistry A European J

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“…MMP-TIMP imbalance results in matrix proteolysis associated with various pathological processes, such as tumor invasion. The potential of MMPs and TIMPs as new therapeutic agents for cancer has been also discussed [37][38][39]. The invasion by cancer cells of surrounding tissues is strongly connected with interactions that occur between invasive cancer cells, cells producing various MMPs (such as endothelial, stromal, and neutrophils cells and macrophages), and cells producing TIMPs (such as lymphocytes, monocytes, macrophages, and mast cells) [40].…”

Section: Timps-characteristic and Classificationmentioning

confidence: 99%

Selected Matrix Metalloproteinases (MMP-2, MMP-7) and Their Inhibitor (TIMP-2) in Adult and Pediatric Cancer

et al. 2020

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The tumor microenvironment (TME) consists of numerous biologically relevant elements. One of the most important components of the TME is the extracellular matrix (ECM). The compounds of the ECM create a network that provides structural and biochemical support to surrounding cells. The most important substances involved in the regulation of the ECM degradation process are matrix metalloproteinases (MMPs) and their endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs). The disruption of the physiological balance between MMP activation and deactivation could lead to progression of various diseases such as cardiovascular disease, cancer, fibrosis arthritis, chronic tissue ulcers, pathologies of the nervous system (such as stroke and Alzheimer’s disease), periodontitis, and atheroma. MMP-TIMP imbalance results in matrix proteolysis associated with various pathological processes such as tumor invasion. The present review discusses the involvement of two MMPs, MMP-2 and MMP-7, in cancer pathogenesis. These two MMPs have been proven in several studies, conducted mostly on adults, to make an important contribution to cancer development and progression. In the current review, several studies that indicate the importance of MMP-TIMP balance determination for the pediatric population are also highlighted. The authors of this review believe that carrying out biochemical and clinical studies focused on metalloproteinases and their inhibitors in tumors in children will be of great relevance for future patient diagnosis, determination of a prognosis, and monitoring of therapy.

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“…Furthermore, six of seven disulfide interdomain bridges are formed among the cysteine residues in the FN2 domain fix (the folded structure) and facilitate pro-MMP-9 secretion [30]. The HX domain (locating 494−538 aa, 540−581 aa, 586−632 aa, and 634−674 aa) near the C-terminal is critical to bind TIMPs or other receptors (e.g., α4β1) [31,32]. The sequence of NtMMP-9 (No.…”

Section: Cloning and Characterization Of Ntmmp-9mentioning

confidence: 99%

“…Compared with interactions between aNtMMP-9 and DCN, aNtMMP-9 interacting with TIMP-2 also produces a complex through binding forces, including hydrophobic interactions and hydrogen bonds instead of anion-π ( Figure 4B and Table S4). TIMPs inhibit active MMPs by binding to catalytic sites of MMPs to maintain the balance of MMPs and TIMPs, which benefits the degrading extent of ECM [4,31]. Probably, more hydrogen bonds have a potential to favor the inhibition of TIMP-2 to MMP-9.…”

Section: Protein-protein Interactions and Molecular Dockingmentioning

confidence: 99%

“…The qPCR detection of NtMMP-9 for all examined tissues of healthy fish using the CFX96 Touch™ Real-Time PCR detection system (Bio-Rad, USA) indicates that the higher transcriptional levels of NtMMP-9 occurred in gill (49.87 ± 0.1 fold), head kidney (27.09 ± 5.86 fold), and spleen (17.34 ± 3.24 fold) compared to that in the intestines (as the control) ( Figure S4); whereas they were lower, but still significant, in both the liver Compared with interactions between aNtMMP-9 and DCN, aNtMMP-9 interacting with TIMP-2 also produces a complex through binding forces, including hydrophobic interactions and hydrogen bonds instead of anion-π ( Figure 4B and Table S4). TIMPs inhibit active MMPs by binding to catalytic sites of MMPs to maintain the balance of MMPs and TIMPs, which benefits the degrading extent of ECM [4,31]. Probably, more hydrogen bonds have a potential to favor the inhibition of TIMP-2 to MMP-9.…”

Section: Transcriptional Expression Of Ntmmp-9mentioning

confidence: 99%

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Characterization of Matrix Metalloprotease-9 Gene from Nile tilapia (Oreochromis niloticus) and Its High-Level Expression Induced by the Streptococcus agalactiae Challenge

et al. 2020

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The bacterial diseases of tilapia caused by Streptococcus agalactiae have resulted in the high mortality and huge economic loss in the tilapia industry. Matrix metalloproteinase-9 (MMP-9) may play an important role in fighting infection. However, the role of MMP-9 in Nile tilapia against S. agalactiae is still unclear. In this work, MMP-9 cDNA of Nile tilapia (NtMMP-9) has been cloned and characterized. NtMMP-9 has 2043 bp and encodes a putative protein of 680 amino acids. NtMMP-9 contains the conserved domains interacting with decorin and inhibitors via binding forces compared to those in other teleosts. Quantitative real-time-polymerase chain reaction (qPCR) analysis reveals that NtMMP-9 distinctly upregulated following S. agalactiae infection in a tissue- and time-dependent response pattern, and the tissues, including liver, spleen, and intestines, are the major organs against a S. agalactiae infection. Besides, the proteolytic activity of NtMMP-9 is also confirmed by heterologous expression and zymography, which proves the active function of NtMMP-9 interacting with other factors. The findings indicate that NtMMP-9 was involved in immune responses against the bacterial challenge at the transcriptional level. Further work will focus on the molecular mechanisms of NtMMP-9 to respond and modulate the signaling pathways in Nile tilapia against S. agalactiae invasion and the development of NtMMP-9-related predictive biomarkers or vaccines for preventing bacterial infection in the tilapia industry.

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Inhibitory Antibodies Designed for Matrix Metalloproteinase Modulation

Cited by 43 publications

References 114 publications

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

Selected Matrix Metalloproteinases (MMP-2, MMP-7) and Their Inhibitor (TIMP-2) in Adult and Pediatric Cancer

Characterization of Matrix Metalloprotease-9 Gene from Nile tilapia (Oreochromis niloticus) and Its High-Level Expression Induced by the Streptococcus agalactiae Challenge

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