Key Points
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Historically, testing matrix metalloproteinase inhibitors (MMPIs) for the therapy of invasive or metastatic cancers has not yielded the expected beneficial results, but has had a positive effect on the development of MMPIs. However, cancers are genetically unstable and more heterogeneous, which implies that the treatment outcomes are less predictable than in inflammation. In addition, it is not clear whether inflammatory cell infiltrations in cancers have beneficial or detrimental roles for the host.
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Seminal work on inflammation and vascular MMP biology is reviewed here and indicates a further need to test MMPIs in established and new animal models of inflammation, infection and ischaemia. In analogy with inducible cyclooxygenase as a drug target, inducible MMPs are preferred above constitutive or homeostatic enzymes to target with MMPIs in inflammatory and vascular diseases.
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In contrast to microbiological enzyme targets, MMPs are host enzymes. This implies that with MMPI treatment, normal physiological functions will be blocked with subsequent side effects. Such side effects are, however, tolerable in life-saving situations.
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In acute life-threatening inflammation, oral use and high selectivity of MMPIs — set as unreached double challenges in the development of MMPIs for cancer treatment — are not necessary. This implies that obligately parenteral drugs, including recombinant proteins (for example, interferon affecting the tissue inhibitor of matrix metalloproteinase (TIMP)/MMP balance) and monoclonal antibodies that inhibit MMPs and peptide MMPIs, are worthwhile to develop and to combine.
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For chronic inflammatory diseases, the picture is completely different to acute inflammation. High selectivity and oral availability are in demand. These diseases constitute important targets for the pharmaceutical industry. Therefore, major basic and animal research efforts need to be continued and extended.
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For vascular diseases, the primary question of whether to use MMPIs relates to the aetiology of the pathology and the localization of the injury. Acute ischaemic insults might benefit from MMPI treatment by the rescue of tissue in the penumbra zones. Long-term treatment of chronic ischaemia with MMPIs will necessitate the development of novel oral, highly selective MMPIs.
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Studies with Mmp-knockout mice contribute to novel insights and are a reasonable indicator to discover whether selective MMPIs have potential benefit. However, acute and chronic inflammatory and vascular animal models have not been sufficiently studied, yielded sometimes discrepant data and are prone to compensatory mechanisms and strain-specific differences. The development of inducible and multiple Mmp-knockout mice, studies of various strain backcrosses and better complementation of data might overcome some of these problems.
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From animal models of organ-specific and tissue-specific acute inflammation and ischaemia the general view is that specific MMPs dominate in the pathogenesis, for example, MMP12 in lung emphysema and MMP9 in acute ischaemia and multiple sclerosis. MMP9 has been studied most as an inducible drug target and many (unspecific) inhibitors against MMP9 have been synthesized and are reviewed. Efforts to generate the complete, rather than partial, MMP crystal structures, molecular modelling and empirical inhibitor screening studies need to be combined with extensive animal experiments for the discovery of novel highly specific and therapeutically active inhibitors.
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For development of synthetic MMPIs, high-affinity zinc-binding groups, mainly hydroxamates, have been preferred. With the discovery of zinc-containing ADAMs (a disintegrin and metalloproteinases) and ADAMTSs (ADAMs with a thrombospondin motif) and their evolving roles in biology and pathology, other determinants for the binding of inhibitors to MMPs, including the active-site pockets and exosites, need to be further investigated. Protein domain specificity, pH dependence of carboxylates and better substrate-based design might be exploited in future directions for MMPI development.
Abstract
Matrix metalloproteinases (MMPs) have outgrown the field of extracellular-matrix biology and have progressed towards being important regulatory molecules in cancer and inflammation. This rise in status was accompanied by the development of various classes of inhibitors. Although clinical trials with synthetic inhibitors for the treatment of cancer were disappointing, recent data indicate that the use of selective inhibitors might lead to new therapies for acute and chronic inflammatory and vascular diseases. In this Review, we compare the major classes of MMP inhibitors and advocate that future drug discovery should be based on crucial insights into the differential roles of specific MMPs in pathophysiology obtained with animal models, including knockout studies.
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Acknowledgements
This Review focuses on inflammatory and vascular diseases rather than on cancer. This implies that major cancer biology literature is not covered, for which we apologize. The present study was supported by the Fund for Scientific Research–Flanders (FWO–Vlaanderen), the Geconcerteerde OnderzoeksActies (GOA 2007-2011), the Rega Centre of Excellence (COE 05/015), the Charcot Foundation and the Belgian Foundation against Cancer. P.V.D.S. is a postdoctoral fellow of the FWO–Vlaanderen. All authors appreciate the excellent scientific help and editorial assistance of M. D. Roycik and S. Lee of Q.-X. Sang's laboratory, and V. Dubois of G.O.'s laboratory. This article is dedicated to the late Ofer Lider of the Weizmann Institute of Science, in memory of his friendship and his insights that the environmental contexts need to be better investigated and understood before any intervention whatsoever.
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Supplementary information
Supplementary information S1 (box)
Structure activity relations of MMP inhibitor classes (PDF 1533 kb)
Supplementary information S2 (table)
Overview of gelatinase B–/MMP–9–inhibitors in biology. (PDF 596 kb)
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DATABASES
OMIM
chronic obstructive pulmonary disease
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Department of Chemistry and Biochemistry, Florida State University
Glossary
- Tissue inhibitors of metalloproteinases
-
Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs). Four are present in humans. This redundancy illustrates the importance of the fine-tuning needed for MMP inhibitors. Some TIMPs possess other functions than regulation of extracellular matrix turnover.
- Chemokines
-
A family of structurally related, small proteins that have potent chemotactic activity and mediate migration of inflammatory cells from blood vessels to the site of inflammation and leukocyte homing.
- Atherosclerosis
-
Atherosclerosis starts by the formation of a fatty streak, an accumulation of lipid-loaded macrophages in the tunica intima. The fatty streak evolves into an atherosclerotic plaque by the migration and proliferation of smooth muscle cells, the formation of a necrotic core and a fibrous cap with extracellular matrix components.
- Substrate-based design
-
Substrate-based design of hydrolase inhibitors is done on the basis of the definition of characteristics of preferred substrates. Shared properties of such substrates are used as anchor points in the design of inhibitors. Usually the scissile bond between P1 and P1′ is chemically modified to prevent the hydrolysis of the substrate.
- Structure-based design
-
Structure-based design of enzyme inhibitors uses the three-dimensional structural information of the catalytic site of an enzyme. With the use of molecular-modelling techniques, series of possible small-inhibitor structures are docked into the active site and selected.
- Tetracyclines and derivatives.
-
Tetracyclines and chemically modified tetracyclines (CMTs) have been used to counteract extracellular matrix turnover and as anti-inflammatory agents. The binding of tetracycline and CMTs with pro- or active matrix metalloproteinases (MMPs) results in the disruption of the normal conformation of the protein structure and leaves the enzymes inactive and therefore vulnerable to degradation into small molecule fragments. CMTs have also been shown to downregulate gene expression of particular MMPs.
- Neutrophils
-
Neutrophils are the most abundant cell type in the human circulation. Lipopolysaccharide acts directly on these cells in endotoxinaemia. This results in the release of pro-matrix metalloproteinase 8 (MMP8) and pro-MMP9, which are activated by, for example, reactive oxygen intermediates, and of lysozyme, which generates peptidoglycan fragments. An important aspect of endotoxinaemia and septic shock is its acuteness, based on fast degranulation of the neutrophils.
- Foamy macrophages
-
Macrophages in the arterial wall that ingest oxidized low-density lipoprotein and assume a foamy appearance. These cells secrete various substances involved in further plaque growth.
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Hu, J., Van den Steen, P., Sang, QX. et al. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6, 480–498 (2007). https://doi.org/10.1038/nrd2308
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DOI: https://doi.org/10.1038/nrd2308
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