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Chemistry (Weinheim An Der Bergstrasse,... Jun 2019Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug-discovery programs have not... (Review)
Review
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.
Topics: Animals; Drug Design; Drug Discovery; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Models, Molecular; Structure-Activity Relationship
PubMed: 30720221
DOI: 10.1002/chem.201805361 -
Life Sciences Oct 2019Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA... (Review)
Review
Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA results in the loss of joint function, usually accompanied by severe pain, and are the most common type of arthritis, affecting more than 10% of adults. The characteristic signs of OA are progressive cartilage destruction and, eventually, complete loss of chondrocytes. A key enzyme responsible for these degenerative changes in cartilage is matrix metalloproteinase-13 (MMP-13), which is thought to be a major contributor to the degenerative process occurring during OA pathogenesis. The aim of the present review is to shed light on the general role of MMPs, with special emphasis on MMP-13, in the induction of OA and the general basis of OA treatment. The pathogenic mechanism of this highly prevalent disease is not clear, and no effective disease-modifying treatment is currently available. Any updated information about OA treatment in human patients will also benefit companion animals such as horses and dogs, which also suffer from OA. Selective inhibition of MMP-13 seems to be an attractive therapeutic strategy.
Topics: Animals; Cartilage, Articular; Drug Discovery; Extracellular Matrix; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Osteoarthritis
PubMed: 31445934
DOI: 10.1016/j.lfs.2019.116786 -
International Journal of Molecular... Jun 2020In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of... (Review)
Review
In industrialized countries, cancer is the second leading cause of death after cardiovascular disease. Most cancer patients die because of metastases, which consist of the self-transplantation of malignant cells in anatomical sites other than the one from where the tumor arose. Disseminated cancer cells retain the phenotypic features of the primary tumor, and display very poor differentiation indices and functional regulation. Upon arrival at the target organ, they replace preexisting, normal cells, thereby permanently compromising the patient's health; the metastasis can, in turn, metastasize. The spread of cancer cells implies the degradation of the extracellular matrix by a variety of enzymes, among which the matrix metalloproteinase (MMP)-9 is particularly effective. This article reviews the available published literature concerning the important role that MMP-9 has in the metastatic process. Additionally, information is provided on therapeutic approaches aimed at counteracting, or even preventing, the development of metastasis via the use of MMP-9 antagonists.
Topics: Cell Line, Tumor; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms
PubMed: 32630531
DOI: 10.3390/ijms21124526 -
International Journal of Molecular... Jan 2023A protease is an enzyme with a proteolytic activity that facilitates the digestion of its substrates. Membrane-type I matrix metalloproteinase (MT1-MMP), a member of the... (Review)
Review
A protease is an enzyme with a proteolytic activity that facilitates the digestion of its substrates. Membrane-type I matrix metalloproteinase (MT1-MMP), a member of the broader matrix metalloproteinases (MMP) family, is involved in the regulation of diverse cellular activities. MT1-MMP is a very well-known enzyme as an activator of pro-MMP-2 and two collagenases, MMP-8 and MMP-13, all of which are essential for cell migration. As an anchored membrane enzyme, MT1-MMP has the ability to interact with a diverse group of molecules, including proteins that are not part of the extracellular matrix (ECM). Therefore, MT1-MMP can regulate various cellular activities not only by changing the extra-cellular environment but also by regulating cell signaling. The presence of both intracellular and extra-cellular portions of MT1-MMP can allow it to interact with proteins on both sides of the cell membrane. Here, we reviewed the MT1-MMP substrates involved in disease pathogenesis.
Topics: Collagenases; Matrix Metalloproteinase 14; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Proteins; Substrate Specificity
PubMed: 36768503
DOI: 10.3390/ijms24032183 -
Advances in Pharmacology (San Diego,... 2018Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocytes. MMPs are regulated at the level of mRNA expression and by activation through removal of the propeptide domain from their latent zymogen form. MMPs are often secreted in an inactive proMMP form, which is cleaved to the active form by various proteinases including other MMPs. MMPs degrade various protein substrates in ECM including collagen and elastin. MMPs could also influence endothelial cell function as well as VSM cell migration, proliferation, Ca signaling, and contraction. MMPs play a role in vascular tissue remodeling during various biological processes such as angiogenesis, embryogenesis, morphogenesis, and wound repair. Alterations in specific MMPs could influence arterial remodeling and lead to various pathological disorders such as hypertension, preeclampsia, atherosclerosis, aneurysm formation, as well as excessive venous dilation and lower extremity venous disease. MMPs are often regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs may serve as biomarkers and potential therapeutic targets for certain vascular disorders.
Topics: Animals; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Substrate Specificity; Tissue Distribution; Vascular Diseases; Vascular Remodeling
PubMed: 29310800
DOI: 10.1016/bs.apha.2017.08.002 -
Critical Reviews in Eukaryotic Gene... 2008Matrix metalloproteinases (MMPs) play crucial roles in a variety of normal (e.g., blood vessel formation, bone development) and pathophysiological (e.g., wound healing,... (Review)
Review
Matrix metalloproteinases (MMPs) play crucial roles in a variety of normal (e.g., blood vessel formation, bone development) and pathophysiological (e.g., wound healing, cancer) processes. This is not only due to their ability to degrade the surrounding extracellular matrix (ECM), but also because MMPs function to reveal cryptic matrix binding sites, release matrix-bound growth factors inherent to these processes, and activate a variety of cell surface molecules. The process of blood vessel formation, in particular, is regulated by what is widely classified as the angiogenic switch: a mixture of both pro- and antiangiogenic factors that function to counteract each other unless the stimuli from one side exceeds the other to disrupt the quiescent state. Although it was initially thought that MMPs were strictly proangiogenic, new functions for this proteolytic family, such as mediating vascular regression and generating matrix fragments with antiangiogenic capacities, have been discovered in the last decade. These findings cast MMPs as multifaceted pro- and antiangiogenic effectors. The purpose of this review is to introduce the reader to the general structure and characterization of the MMP family and to discuss the temporal and spatial regulation of their gene expression and enzymatic activity in the following crucial steps associated with angiogenesis: degradation of the vascular basement membrane, proliferation and invasion of endothelial cells within the subjacent ECM, organization into immature tubules, maturation of these nascent vessels, and the pruning and regression of the vascular network.
Topics: Angiogenesis Inhibitors; Animals; Capillaries; Cell Proliferation; Endothelial Cells; Extracellular Matrix; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Morphogenesis
PubMed: 18540825
DOI: 10.1615/critreveukargeneexpr.v18.i3.30 -
Molecules (Basel, Switzerland) Nov 2019Fibrosis is a type of chronic organ failure, resulting in the excessive secretion of extracellular matrix (ECM). ECM protects wound tissue from infection and additional... (Review)
Review
Fibrosis is a type of chronic organ failure, resulting in the excessive secretion of extracellular matrix (ECM). ECM protects wound tissue from infection and additional injury, and is gradually degraded during wound healing. For some unknown reasons, myofibroblasts (the cells that secrete ECM) do not undergo apoptosis; this is associated with the continuous secretion of ECM and reduced ECM degradation even during de novo tissue formation. Thus, matrix metalloproteinases (MMPs) are considered to be a potential target of fibrosis treatment because they are the main groups of ECM-degrading enzymes. However, MMPs participate not only in ECM degradation but also in the development of various biological processes that show the potential to treat diseases such as stroke, cardiovascular diseases, and arthritis. Therefore, treatment involving the targeting of MMPs might impede typical functions. Here, we evaluated the links between these MMP functions and possible detrimental effects of fibrosis treatment, and also considered possible approaches for further applications.
Topics: Animals; Disease Susceptibility; Enzyme Activation; Extracellular Matrix; Fibrosis; Gene Expression Regulation; Humans; Immunomodulation; Matrix Metalloproteinases; Myofibroblasts; Neovascularization, Pathologic; Organ Specificity; Proteolysis; Wound Healing
PubMed: 31752262
DOI: 10.3390/molecules24224188 -
Journal of Pharmacological and... 2010Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases capable of degrading extracellular matrix, including the basement membrane. MMPs are associated with... (Review)
Review
INTRODUCTION
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases capable of degrading extracellular matrix, including the basement membrane. MMPs are associated with various physiological processes such as morphogenesis, angiogenesis, and tissue repair. Moreover, due to the novel non-matrix related intra- and extracellular targets of MMPs, dysregulation of MMP activity has been implicated in a number of acute and chronic pathological processes, such as arthritis, acute myocardial infarction, chronic heart failure, chronic obstructive pulmonary disease, inflammation, and cancer metastasis. MMPs are considered as viable drug targets in the therapy of the above diseases.
METHODS
For the development of selective MMP inhibitor molecules, reliable methods are necessary for target validation and lead development. Here, we discuss the major methods used for MMP assays, focusing on substrate zymography. We highlight some problems frequently encountered during sample preparations, electrophoresis, and data analysis of zymograms.
RESULTS AND DISCUSSION
Zymography is a widely used technique to study extracellular matrix-degrading enzymes, such as MMPs, from tissue extracts, cell cultures, serum or urine. This simple and sensitive technique identifies MMPs by the degradation of their substrate and by their molecular weight and therefore helps to understand the widespread role of MMPs in different pathologies and cellular pathways.
Topics: Animals; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Fluorescence Resonance Energy Transfer; Humans; Matrix Metalloproteinases; Substrate Specificity
PubMed: 20176119
DOI: 10.1016/j.vascn.2010.02.011 -
Expert Opinion on Drug Discovery Jan 2018The overexpression of matrix metalloproteinase (MMP) plays an important role in the context of tumor invasion and metastasis, and MMP-2 has been characterized as the... (Review)
Review
The overexpression of matrix metalloproteinase (MMP) plays an important role in the context of tumor invasion and metastasis, and MMP-2 has been characterized as the most validated target for cancer. Therefore, it is necessary to design matrix metalloproteinase inhibitors (MMPIs) that would be active and selective against MMP-2 but non-selective toward other MMPs. Areas covered: This article clearly describes the structural character of MMP-2 followed by a review of the recent development of selective MMP-2 inhibitors based on their basic structures. Expert opinion: Over the past 30 years, MMPs have been considered to be attractive cancer targets, and several different types of synthetic inhibitors have been identified as anticancer agents, but only a small number of small MMPIs have been examined in clinical trials, and none of these molecules has been established as anticancer drugs due to their adverse effects. One major possibility is that the MMPIs used in clinical trials were broad-spectrum drugs that also inhibited the anti-tumor effects and influenced the mediation of the normal physiological processes of MMPs. MMP-2 has recently been characterized as the most validated target for cancer. Therefore, the design and synthesis of selective MMP-2 inhibitors would be helpful for the treatment of cancer.
Topics: Animals; Antineoplastic Agents; Drug Design; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Targeted Therapy; Neoplasms
PubMed: 29088927
DOI: 10.1080/17460441.2018.1398732 -
Biochimica Et Biophysica Acta. Proteins... Jun 2020Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin,... (Review)
Review
Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.
Topics: Actinobacteria; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Movement; Cyclohexanones; Glyoxylates; Humans; Matrix Metalloproteinase 11; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Models, Molecular; NF-kappa B; NF-kappa B p50 Subunit; Neoplasm Invasiveness; Neoplasms; Quinones
PubMed: 32179183
DOI: 10.1016/j.bbapap.2020.140412