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Matrix Metalloproteinases as Valid Clinical Target
Abstract and Figures
The matrix metalloproteinase family of enzymes has been a pharmaceutical target for over 20 years. In that time, many drugs have been developed but none have successfully passed clinical trials. A significant problem has been development of dose-limiting side-effects that were revealed during long-term clinical trials in diseases such as arthritis and various cancers. There are, however, other clinical settings where evidence for MMP function contributing to the pathophysiology of disease is strong. A number of these settings will be discussed here together with evidence from animal models that MMP inhibition is a valid strategy to be considered. A major advantage with many of these settings is that drug exposure may not have to be long-term and/or systemic thus reducing the possibility that side-effects will stymie MMPI-based therapy.
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... Флавоноиды и подобные структуры (рис. 5) [28][29][30]: агеладин A -флуоресцентный алкалоид, выделенный из морской губки, ингибирует MMП-1, -8, -9, -12, и -13 со значением IC 50 = 1,2; 0,39; 0,79; 0,33, и 0,47 мг/мл, соответственно; генистеин -(4H-1-бензоперан-4-он-5,7-дигидрокси-3-4 гидроксифенил) изофлавонид, промежуточное вещество в синтезе других изофлавонидов, защищающих растения от микробов [28]. Содержится в сое, является ингибитором желатиназ, при этом способствует выделению ТИММП-1. ...
... Флавоноиды и подобные структуры (рис. 5) [28][29][30]: агеладин A -флуоресцентный алкалоид, выделенный из морской губки, ингибирует MMП-1, -8, -9, -12, и -13 со значением IC 50 = 1,2; 0,39; 0,79; 0,33, и 0,47 мг/мл, соответственно; генистеин -(4H-1-бензоперан-4-он-5,7-дигидрокси-3-4 гидроксифенил) изофлавонид, промежуточное вещество в синтезе других изофлавонидов, защищающих растения от микробов [28]. Содержится в сое, является ингибитором желатиназ, при этом способствует выделению ТИММП-1. ...
Metalloproteinase was discovered by Gross and Lapierre in 1962 for the first time. Since then, more than 20 enzymes of this family have been characterized, and their functions have been studied in detail. Metalloproteinases take part in blood pressure regulation, the cell matrix extension and remodeling, anesthesia, multiple sclerosis, blood coagulation, wound healing, tumor transformation and metastasis, etc. This review covers structure of
matrix metalloproteinases, their mechanism of action, as well as MMP`s endogenous and exogenous inhibitors. A special place is occupied by analysis of approaches to matrix metalloproteinases synthetic inhibitors and their activity. This review demonstrates the perspectivity of new selective matrix metalloproteinase inhibitors design.
... Invasion of malignant cells into basement membrane and surrounding healthy tissue, influx of neoplastic cells into lymphatics and blood arteries, and metastasis to distant organs are all facilitated by proteolytic enzymes [8,15,22]. According to studies Björklund M [15], Fingleton [23], Biljana E [24], tumor progression necessitates the cleavage and activation of growth factors, proteinases and their inhibitors, blood clotting factors, cell surface receptors, adhesion molecules, and intracellular substrates, followed by the cleavage of extracellular matrix components. Proteases were subsequently presented as useful tumor indicators. ...
A class of proteinases called matrix metalloproteinases (MMPs) is involved in the breakdown of the extracellular matrix (ECM) as well as other biological activities. Due to their capacity to degrade the matrix, they were considered in the invasion and metastasis of tumors. The primary goal of this study is to evaluate the association between MMP-9 expression in tumor-adjacent stromal cells and malignant mammary tumors in dogs, as well as the potential use of this protease as a predictive tumor marker. During surgery and necropsy, 32 canine malignant mammary gland tumors were discovered. For histopathological grading of tumors, the Pena et al. [1], approach and the Goldsmith et al. [2], method were employed. Utilizing immunohistochemical labeling, epithelial and stromal cell MMP-9 expression was identified. The level of tumor malignancy was associated with the degree of MMP-9 expression in stromal cells. In addition, stromal cells had much greater levels of MMP-9 expression. The expression of MMP-9 was well distributed and intense in all grade II and III carcinomas as well as poorly differentiated carcinosarcomas. High histologic grade tumors have greater levels of MMP-9 expression, according to semiquantitative examination of the gene’s expression. This finding lends credence to the concept that MMP-9 functions as an ECM component in tumor invasion and metastasis.
... Invasion of malignant cells into basement membrane and surrounding healthy tissue, influx of neoplastic cells into lymphatics and blood arteries, and metastasis to distant organs are all facilitated by proteolytic enzymes [8,15,22]. According to studies Björklund M [15], Fingleton [23], Biljana E [24], tumor progression necessitates the cleavage and activation of growth factors, proteinases and their inhibitors, blood clotting factors, cell surface receptors, adhesion molecules, and intracellular substrates, followed by the cleavage of extracellular matrix components. Proteases were subsequently presented as useful tumor indicators. ...
A class of proteinases called matrix metalloproteinases (MMPs) is involved in the breakdown of the extracellular matrix (ECM) as well as other biological activities. Due to their capacity to degrade the matrix, they were considered in the invasion and metastasis of tumors. The primary goal of this study is to evaluate the association between MMP-9 expression in tumor-adjacent stromal cells and malignant mammary tumors in dogs, as well as the potential use of this protease as a predictive tumor marker. During surgery and necropsy, 32 canine malignant mammary gland tumors were discovered. For histopathological grading of tumors, the Pena et al. [1], approach and the Goldsmith et al. [2], method were employed. Utilizing immunohistochemical labeling, epithelial and stromal cell MMP-9 expression was identified. The level of tumor malignancy was associated with the degree of MMP-9 expression in stromal cells. In addition, stromal cells had much greater levels of MMP-9 expression. The expression of MMP-9 was well distributed and intense in all grade II and III carcinomas as well as poorly differentiated carcinosarcomas. High histologic grade tumors have greater levels of MMP-9 expression, according to semiquantitative examination of the gene's expression. This finding lends credence to the concept that MMP-9 functions as an ECM component in tumor invasion and metastasis.
... The overexpression of MMPs in infarcted myocardium promotes ECM degradation and diminishes the mechanical properties of the ventricular wall, thereby resulting in progressive thinning and global dilatation of infarcted areas. Consequently, MMP levels have been used as a marker of HF [93]. For targeted inhibition of MMP expression and activity, the design of injectable hydrogels capable of regulating MMP levels has become a commonly used strategy for MI treatment. ...
Myocardial infarction (MI) triggers adverse remodeling mechanisms, thus leading to heart failure. Since the application of biomaterial-based scaffolds emerged as a viable approach for providing mechanical support and promoting cell growth, injectable hydrogels have garnered substantial attention in MI treatment because of their minimally invasive administration through injection and diminished risk of infection. To fully understand the interplay between injectable hydrogels and infarcted myocardium repair, this review provides an overview of recent advances in injectable hydrogel-mediated MI therapy, including: I) material designs for repairing the infarcted myocardium, considering the pathophysiological mechanism of MI and design principles for biomaterials in MI treatment; II) the development of injectable functional hydrogels for MI treatment, including conductive, self-healing, drug-loaded, and stimulus-responsive hydrogels; and III) research progress in using injectable hydrogels to restore cardiac function in infarcted myocardium by promoting neovascularization, enhancing cardiomyocyte proliferation, decreasing myocardial fibrosis, and inhibiting excessive inflammation. Overall, this review presents the current state of injectable hydrogel research in MI treatment, offering valuable information to facilitate interdisciplinary knowledge transfer and enable the development of prognostic markers for suitable injectable materials.
... Matrix metalloproteinases (MMPs), degrading various components of extracellular matrix (ECM), are found to be crucially interlinked with the modulation of normal physiological processes as well as versatile pathophysiological conditions and thus, have been established as promising biomolecular targets for the design and development of potential drug candidates to get rid of numerous lifethreatening diseases [1]. In this context, the process of development of matrix metalloproteinase inhibitors (MMPIs) was initiated more than 30 years ago and continued to date [2][3][4]. ...
Introduction:
Matrix metalloproteinases (MMPs) are strongly interlinked with the progression and mechanisms of several life-threatening diseases including cancer. Thus, novel MMP inhibitors (MMPIs) as promising drug candidates can be effective in combating these diseases. However, no MMPIs are marketed to date due to poor pharmacokinetics and lower selectivity. Therefore, this review was performed to study the newer MMPIs patented after the COVID-19 period for an updated perspective on MMPIs.
Areas covered:
This review highlights patents related to MMPIs, and their therapeutic implications published between January 2021 and August 2023 available in the Google Patents, Patentscope, and Espacenet databases.
Expert opinion:
Despite various MMP-related patents disclosed up to 2020, newer patent applications in the post-COVID-19 period decreased a lot. Besides major MMPs, other isoforms (i.e. MMP-3 and MMP-7) have gained attention recently for drug development. This may open up newer dimensions targeting these MMPs for therapeutic advancements. The isoform selectivity and bioavailability are major concerns for effective MMPI development. Thus, adopting theoretical approaches and experimental methodologies can unveil the development of novel MMPIs with improved pharmacokinetic profiles. Nevertheless, the involvement of MMPs in cancer, and the mechanisms of such MMPs in other diseases should be extensively studied for novel MMPI development.
... Data from mouse models are used to answer questions regarding a single process or organ system, not the body as a whole, which is a major distinction between rodents and humans. This may explain the incorrect predictions [50]. Therefore, new animal-free models need to be developed to fulfil the ...
Breast cancer is the most common ailment among women. In 2020, it had the highest incidence of any type of cancer. Many Phase II and III anti-cancer drugs fail due to efficacy, durability, and side effects. Thus, accelerated drug screening models must be accurate. In-vivo models have been used for a long time, but delays, inconsistent results, and a greater sense of responsibility among scientists toward wildlife have led to the search for in-vitro alternatives. Stromal components support breast cancer growth and survival. Multi-compartment Transwell models may be handy instruments. Co-culturing breast cancer cells with endothelium and fibroblasts improves modelling. The extracellular matrix (ECM) supports native 3D hydrogels in natural and polymeric forms. 3D Transwell cultured tumor spheroids mimicked in-vivo pathological conditions. Tumor invasion, migration, Trans-endothelial migration, angiogenesis, and spread are studied using comprehensive models. Transwell models can create a cancer niche and conduct high-throughput drug screening, promising future applications. Our comprehensive shows how 3D in-vitro multi compartmental models may be useful in producing breast cancer stroma in Transwell culture.
... only additional signals such as tissue injury or cytokine signaling result in enhanced MMP gene transcription and/or enzyme activation. 34 our data show a significant positive correlation between plasma Discussion chd is the term used to describe the condition that develops when the coronary arteries that supply the heart with oxygen and nutrients become so narrowed that insufficient blood gets through. this damage is usually the result of inflammation and cholesterol-containing deposits (called plaques) forming in coronary arteries. ...
Influenza viruses constitute a significant threat to public health worldwide over many decades, and continue to inflict significant morbidity and mortality. Previous studies show that infection of mice with mouse-adapted influenza A/Aichi/2/1968(H3N2) passage 10 (P10) virus can elicit exuberant inflammatory responses in the lungs with extensive infiltration of macrophages and neutrophils (which are sources of gelatinases) that contribute to pulmonary damage. The lungs of mice with severe influenza pneumonitis also reveal extensive neutrophilic infiltration, neutrophil extracellular traps (NETs), alveolar damage, heightened viral load, and pathologic features of acute respiratory distress syndrome (ARDS). Excessive neutrophil and matrix metalloproteinase (MMP) activities are implicated in the pathogenesis of acute lung injury (ALI) and ARDS. Hence, an objective of this study was to investigate the production of MMP-2 and MMP-9 in neutrophils differentiated from the MPRO murine pro-myelocytic cell line, following infection with mouse-adapted influenza H3N2 virus. Another objective was to investigate the effects of doxycycline on expression of MMP-2 and MMP-9 at transcriptional and translational levels in neutrophils in the context of influenza virus infection. MMP-2 and MMP-9 production and gelatinase activity were found to be induced by infection of differentiated neutrophils with mouse-adapted influenza H3N2 virus. Furthermore, doxycycline treatment was able to abrogate this increase in MMP-2 and MMP-9 expression and gelatinase activity. Given that excessive neutrophil infiltration and uncontrolled neutrophil gelatinase activity in pulmonary tissues play pivotal roles in the pathogenesis of ALI and ARDS, this study offers insights into the mechanism of excessive MMP-2 and MMP-9 production and activity in neutrophils during influenza virus infection. Thus, repurposing doxycycline as an MMP inhibitor represents a potential therapeutic strategy to ameliorate influenza-associated pulmonary injury by targeting MMPs, gelatinase production and activity in neutrophils. Doxycycline therapy (alone or in combination with other drugs) has also been considered and explored for the management of other infectious diseases such as coronavirus infections and tuberculosis.
Matrix metalloproteinases (MMPs) attracted medicinal chemists as they are biological targets that are involved in various pathophysiological processes such as extracellular matrix protein degradation, cell‐surface receptor release and cleavage, tumor growth, homeostatic control, and innate immunity. New heterocycles, bearing both silicon and phosphorus in their molecular structures, were successfully produced via reacting silylated isocyanates and/or isothiocyanates with appropriate phosphorus ylides. Reacting nucleophilic phosphacumulenes (2,6) with isocyanate 1 and isothiocyanate 9 yielded four‐membered ring heterocycles containing phosphorus and silicon (4 and 11) and six‐membered rings heterocycles (5, 8 and 12). Moreover, novel heterocycles containing two phosphorus atoms and one silicon atom were produced by the reaction of diphosphorane 13 with 1 or 9. On the other side, four‐membered (23, 26 and 29a) and six‐membered heterocyclic derivatives (20b and 29b) containing two phosphorus atoms in their structures were also obtained from the reaction of phosphallene ylide 13 and substrates (18, 21, 24 and 27). All the final compounds were tested for their MMP‐2 inhibitor activity showing IC50 values in the range of 0.0408–0.4985 μM. The thiolactam derivative 11 and the azaphosphetidin‐4‐one derivative 15, both bearing silicon and phosphorous, showed the highest activity with IC50 values of 0.0408 and 0.0693 μM, respectively, both are significantly higher than that of quercetin (IC50 = 0.1631 μM). Docking simulations were carried out for the most two active compounds 11 and 15 in the vicinity of the active site of MMP‐2 enzyme and both formed coordinate bonds with the zinc cation key interaction for MMP‐2 enzyme. In conclusion, compounds 11 and 15 can be considered as potential MMP‐2 inhibitors and can be subjected to further studies as antimetastatic agents. Synthesis of new bioactive heterocyclic compounds bearing phosphorus and silicon moieties. The reaction of phosphacumulene and phosphallene ylides with iso(thio)cyanates resulted in the formation of different four‐, and six‐membered heterocyclic compounds containing one phosphorus or two phosphorus atoms. Molecular docking studies are carried out for the most active compounds 11 and 15 which are considered as potential MMP‐2 inhibitors.
This study was designed to investigate possible involvement of type IV collagenolytic matrix metalloproteinases (MMPs; 72-kDa type IV collagenase [MMP-2], 92-kDa type IV collagenase [MMP-9]), and the respective specific tissue inhibitors of these MMPs (TIMP-2 and TIMP-1) in the development of adult respiratory distress syndrome (ARDS). We determined the concentrations of these enzymes in the bronchoalveolar lavage fluid (BALF) from patients with ARDS using newly developed sensitive one-step sandwich enzyme immunoassay methods. BALF obtained from the 17 patients and eight healthy volunteer control subjects were also used for the analysis of the number of the cellular component. Concentrations of the 7S portion of type IV collagen and laminin in the BALF were measured as markers of basement membrane disruption. In the BALF from the ARDS patients, the concentrations of MMP-2 (66.7 +/- 57.0 ng/ml versus < 7.0 ng/ml for controls, p < 0.01) and MMP-9 (118.0 +/- 309.3 ng/ml versus 9.0 +/- 9.5 ng/ml for controls, p < 0.05), and the specific inhibitor of MMP-9 (TIMP-1) (161.0 +/- 145.0 ng/ml versus < 50 ng/ml for controls, p < 0.01) were significantly higher compared with those for healthy control subjects. In the ARDS patients, the concentrations of MMP-2 correlated both with those of 7S collagen and laminin; MMP-9 with the concentration of 7S collagen and the number of neutrophils. These findings suggest that the increased concentration of collagenolytic MMPs in lung plays a role in the pathogenesis of ARDS.
An important step in the cascade leading to neuronal cell death is degradation of laminin and other components of the brain extracellular matrix by microglia-derived proteases. Excitotoxic cell death of murine hippocampal neurones in vivo can be prevented by inhibitors of tissue plasminogen activator (tPA) or by inhibitors of plasmin. Plasmin is a potent activator of the matrix metalloproteinases (MMPs), which are made by resident and recruited leukocytes following CNS injury. In this study, we show, using Taqman RT-PCR, that MMP mRNAs, but not other calcium-dependent proteases such as calpain mRNAs, are acutely up-regulated after an excitotoxic challenge in vivo. ?2-antiplasmin or BB-3103, a broad-spectrum inhibitor of the MMPs, co-injected with kainic acid into the striatum, inhibits excitotoxic cell death in the rat striatum, and reduces both the number of recruited macrophages and the size of the lesion. We also show that leukocyte populations differentially express MMPs, which may account, in part, for the expression profile we observe in the challenged brain. Our results show that inhibition of the MMPs in the rat will prevent kainic acid-induced cell death in the brain. These studies suggest that MMP inhibitors have therapeutic potential for use in stroke, and support the increasing evidence that microglial activation may contribute to neuronal cell death.
Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.
A mouse model involving the human papillomavirus type-16 oncogenes develops cervical cancers by lesional stages analogous to those in humans. In this study the angiogenic-phenotype was characterized, revealing intense angiogenesis in high-grade cervical intraepithelial neoplasias (CIN-3) and carcinomas. MMP-9, a proangiogenic protease implicated in mobilization of VEGF, appeared in the stroma concomitant with the angiogenic switch, expressed by infiltrating macrophages, similar to what has been observed in humans. Preclinical trials sought to target MMP-9 and angiogenesis with a prototypical MMP inhibitor and with a bisphosphonate, zoledronic acid (ZA), revealing both to be antiangiogenic, producing effects comparable to a Mmp9 gene KO in impairing angiogenic switching, progression of premalignant lesions, and tumor growth. ZA therapy increased neoplastic epithelial and endothelial cell apoptosis without affecting hyperproliferation, indicating that ZA was not antimitotic. The analyses implicated cellular and molecular targets of ZA's actions: ZA suppressed MMP-9 expression by infiltrating macrophages and inhibited metalloprotease activity, reducing association of VEGF with its receptor on angiogenic endothelial cells. Given its track record in clinical use with limited toxicity, ZA holds promise as an "unconventional" MMP-9 inhibitor for antiangiogenic therapy of cervical cancer and potentially for additional cancers and other diseases where MMP-9 expression by infiltrating macrophages is evident.
The matrix metalloproteinases (MMPs) have been viewed as bulldozers, destroying the extracellular matrix to permit normal remodeling and contribute to pathological tissue destruction and tumor cell invasion. More recently, the identification of specific matrix and non-matrix substrates for MMPs and the elucidation of the biological consequence of cleavage indicates that perhaps MMPs should be viewed more as pruning shears, playing sophisticated roles in modulating normal cellular behavior, cell–cell communication and tumor progression.
Important concepts underlying the pathophysiology of abdominal aortic aneurysm (AAA) disease include a genetic predisposition, male predominance, and increased proteolysis. Proteolytic activity is carefully controlled by an abundance of protease inhibitors and the increased proteolysis may reflect a decrease in inhibitory activity. The recent assignment for the major tissue inhibitor of metalloproteinases (TIMP) to the X chromosome provides a potential link between the male predominance and increased proteolysis noted in AAA. The purpose of this investigation was to measure the amount of TIMP in normal and diseased aorta. A polyclonal antibody to recombinant human TIMP was produced in rabbit and used to establish an immunoassay. Immunoreactive TIMP in normal and diseased aorta was then measured. There was more TIMP in the matrix-associated fraction than in the soluble fraction. There was significantly less immunoreactive TIMP in aortic extracts from AAA than from control as measured both by Western blot and radioimmunoassay. These results suggest that a diminished amount of TIMP in the aortic matrix in AAA patients may contribute to the increased proteolysis observed in AAA.
It has been hypothesized that emphysema results from damage to the elastic fiber network of the lungs as a result of elastase-antielastase imbalance. We used a new assay for urinary desmosine (DES) and isodesmosine (IDES), specific markers for the degradation of mature crosslinked elastin, and hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP), specific markers for the degradation of mature crosslinked collagen, in order to examine elastin and collagen degradation in relation to current cigarette smoking and the presence of chronic obstructive pulmonary disease (COPD). The study sample consisted of 22 never-smokers (NSM group), 13 current smokers without airflow obstruction (SM group), and 21 patients with COPD (COPD group), including both current and former smokers. The relation between the creatinine-height index and FEV1 was used to correct for possible loss of muscle mass and decreased excretion of creatinine in the COPD group. Mean urinary excretion of elastin-derived crosslinks in the COPD group (DES, 11.8 +/- 5.1 [mean +/- SD]; IDES, 11.3 +/- 5.0 micrograms/g creatinine) and in the SM group (DES, 11.0 +/- 4.2; IDES, 10.2 +/- 2.5 micrograms/g creatinine) was significantly higher than in the NSM group (DES, 7.5 +/- 1.4; IDES, 6.9 +/- 1.3 micrograms/g creatinine). In multivariate analysis, current smoking and the presence of COPD were significantly and independently associated with higher urinary excretion of elastin degradation products, and there was no significant interaction between current smoking and the presence of COPD.(ABSTRACT TRUNCATED AT 250 WORDS)
Although abdominal aortic aneurysms (AAAs) exhibit increased expression of matrix metalloproteinases (MMPs), the functional balance between MMPs and their tissue inhibitors (TIMPs) remains uncertain. This report compares the proteolytic activity in normal aorta, aorto-occlusive disease (AOD), and AAA by use of a novel in situ zymographic technique.
Infrarenal aortic specimens were obtained from 25 patients undergoing surgery for AOD or AAA and were compared with normal aortic tissue (n = 7) obtained from cadavers. Immunohistochemical staining was performed for collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), TIMP-1, and TIMP-2. Net proteolytic activity was determined with in situ zymography whereby aortic sections were incubated on fluorescently labeled substrate. Proteolytic activity was detected under epifluorescent examination. Compared with normal aortic tissue, AOD and AAA tissue demonstrated marked increases in MMP-1 and MMP-3 immunoreactivity, predominantly in the neointima, and modest increases in TIMP-1. MMP-2 was increased in the diseased aortas, and TIMP-2 was abundant in normal, AOD, and AAA samples. Zymography revealed proteolytic activity in AOD and AAA tissues with active digestion of casein and gelatin substrate, particularly on the luminal portion of the specimens. Normal specimens exhibited no lytic activity. Comparison of AOD and AAA specimens revealed no difference in MMP/TIMP immunoreactivity or net proteolytic activity.
MMP expression is markedly increased in AOD and AAA samples, and an imbalance between MMPs and their inhibitors results in similar proteolytic activity. The eventual formation of aneurysmal or occlusive lesions appears not to result from an ongoing difference in the proteolytic pattern.