Abstract
Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. Upregulation of metzincin activity is a major feature in many serious pathologies such as cancer, inflammations, and infections. In the last decades, many classes of small molecules have been developed directed to inhibit these enzymes. The principal shortcomings that have hindered clinical development of metzincin inhibitors are low selectivity for the target enzyme, poor water solubility, and long-term toxicity. Over the last 15 years, a novel approach to improve solubility and bioavailability of metzincin inhibitors has been the synthesis of carbohydrate-based compounds. This strategy consists of linking a hydrophilic sugar moiety to an aromatic lipophilic scaffold. This review aims to describe the development of sugar-based and azasugar-based derivatives as metzincin inhibitors and their activity in several pathological models.
Highlights
Tissue remodeling is a crucial process in various pathological and physiological events in living organisms
Matrix metalloproteinases (MMPs) and A disintegrin and Metalloproteinase (ADAMs) are zinc-dependent endopeptidases belonging to a larger family of proteases known as metzincins
Several molecules have been discovered in the last years as MMP or ADAM inhibitors presenting very high activity in vitro and inadequate selectivity for the target enzyme, poor water solubility, and long-term toxicity
Summary
Tissue remodeling is a crucial process in various pathological and physiological events in living organisms. Protein degradation during tissue turnover is regulated by a multitude of proteases, among which metzincins play an important role. Metzincin superfamily includes metalloproteinases which share a similar catalytic site constituted by a zinc ion, a zinc binding consensus motif, and a specific conserved methionine residue [1]. The consensus motif (HEXXHXXG/NXXH/D) is followed by a structurally conserved methionine which participates in the structural integrity of the catalytic domain [2]. Metzincins are classified in five different subfamilies on the basis of structural similarities: the matrixins (matrix metalloproteinases, MMPs), the serralysins (large bacterial proteinases), the astacins, the pappalysins and the adamalysins (ADAMs (A Disintegrin And Metalloproteinases), and ADAMTSs (ADAMs with thrombospondin motifs) [3]
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