Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics

Abstract

<jats:p>The metalloproteinase (MP) family of zinc-dependent proteases, including matrix metalloproteinases (MMPs), a disintegrin and metalloproteases (ADAMs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) plays a crucial role in the extracellular matrix (ECM) remodeling and degradation activities. A wide range of substrates of the MP family includes ECM components, chemokines, cell receptors, and growth factors. Metalloproteinases activities are tightly regulated by proteolytic activation and inhibition via their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), and the imbalance of the activation and inhibition is responsible in progression or inhibition of several diseases, e.g., cancer, neurological disorders, and cardiovascular diseases. We provide an overview of the structure, function, and the multifaceted role of MMPs, ADAMs, and TIMPs in several diseases via their cellular functions such as proteolysis of other cell signaling factors, degradation and remodeling of the ECM, and other essential protease-independent interactions in the ECM. The significance of MP inhibitors targeting specific MMP or ADAMs with high selectivity is also discussed. Recent advances and techniques used in developing novel MP inhibitors and MP responsive drug delivery tools are also reviewed.</jats:p>

The IMMENSE Study: The Interplay Between iMMune and ENdothelial Cells in Mediating Cardiovascular Risk in Systemic Lupus Erythematosus

“…The evidence that sera from subjects with a low percentage of T ang cells had detrimental effects on HUVEC proliferation and phenotype, differently from sera of those with high T ang cell number, is in agreement with the notion that T ang cells exert a proangiogenic potential. Observed results might have been biased by additional cellular or soluble mediators: indeed, surely T ang do not provide the only determinant of serum cytokine levels and several additional cell types contribute to circulating cytokines such as NK, monocytes and dendritic cells (45,46).…”

Natural Flavones and Flavonols: Relationships among Antioxidant Activity, Glycation, and Metalloproteinase Inhibition

“…AGEs induce the release of inflammatory and degenerative factors, such as interleukin-1β, tumor necrosis factor (TNF)-α [6], and metalloproteinases (MMPs) [7]. The activation of MMPs causes progressive damage to the components of the extracellular matrix (ECM), in particular the degradation of proteoglycans (PGs) and the destruction of collagen, with consequent tissue structural modifications [8][9][10]. Several natural antioxidant polyphenols have been harnessed in the treatment of disorders involving glyco/oxidative processes [11,12].…”

“…Therefore, in the present study, the free radical (ROO• and NO•) scavenger effects of flavones (chrysin, apigenin, luteolin) and flavonols (mirycetin, quercetin, and kaempferol) with a different number of hydroxyl groups in the ring B were evaluated and the resulting data were compared with both in vitro anti-glycation activity and metalloproteinases' inhibition effect. In particular, the inhibition of MMP-1, MMP-13, MMP-2, and MMP-9, the four major matrix metalloproteinases regarded as the most vital enzymes for the degradation of the main constituents of the ECM [8], was evaluated. Furthermore, the correlation among flavones' and flavonols' in vitro activity (antioxidant, anti-glycation, MMPs inhibition activity) and their calculated physico-chemical properties (log P, TPSA, BDE, and IP) was investigated, in an attempt to point out a structure-activity relationship (SAR) that could be useful in the development of cosmetic products aimed at preventing and/or treating skin disorders involving glycation and AGEs' formation.…”

Carborane‐Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron‐Capture Therapy (BNCT)

“…[15] MMPs in particular gelatinases MMP-2 and MMP-9 are known to be overexpressed in tumors as well as in articular cartilage in patients suffering from rheumatoid and osteoarthritis. [16] In order to halt disease progression resulting from exaggerated matrix remodeling mediated by MMPs, MMP inhibitors (MMPi's) have been extensively explored. [17] Elegant EGFR inhibitor [18] and kinase inhibitor [19,20] target-directed BNCT agents have recently been reported by Viñas and colleagues.…”

“…Because the piperidine-N-substituent is directed into solvent and is outside of the enzyme active site, very large groups may be placed in this position without a significant loss of potency [21] and it is this position where we intended to install a carborane moiety. Using this approach, we now report MMP inhibitors employing the pharmacophore of these clinical candidates that bind with high potency to gelatinase enzymes MMP-2 and MMP-9 that are overexpressed [16] in tumors and in arthritic tissues that should be capable of delivering a high density of boron atoms to tumor and/or arthritic tissue, thus enabling a high neutroncapture cross section and binary treatment of tumors using BNCT as well as the treatment of RA with neutron therapy. In addition, these potent inhibitors exhibit a much lower potency at MMP-1, which has been implicated in the muscular skeletal syndrome.…”