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Review
. 2020 Nov 10;13(11):376.
doi: 10.3390/ph13110376.

Developments in Carbohydrate-Based Metzincin Inhibitors

Doretta Cuffaro  1 , Elisa Nuti  1 , Felicia D'Andrea  1 , Armando Rossello  1
Affiliations
Review

Developments in Carbohydrate-Based Metzincin Inhibitors

Doretta Cuffaro et al. Pharmaceuticals (Basel). .

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.

Keywords: ADAMs; MMPs; carbohydrates; glycoconjugates; iminosugars; metzincin inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of the matrix metalloproteinase (MMP) domains and family member classification. SP: signal peptide; Pro: propeptide; TM: transmembrane domain; GPI: glycosylphosphatidylinositol; Cys: cysteine array; Fn: fibronectin repeat; Fr: furin-cleavage site; SH: thiol group.
Figure 2
Figure 2
General representation of amide bond hydrolysis in the catalytic site of MMPs.
Figure 3
Figure 3
Schematic representation of MMP catalytic binding site.
Figure 4
Figure 4
Chemical structure of the most representative zinc-chelating metzincin inhibitors.
Figure 5
Figure 5
Chemical structure of glycoconjugated MMPIs 1–6.
Figure 6
Figure 6
The binding mode of 3 [73] in the MMP-12 catalytic domain (PDB: 3N2U). Image generated with Chimera, version 1.13.
Figure 7
Figure 7
Chemical structure of sugar-based arylsulfonamido MMPIs 8–25 and the parent compound 7.
Figure 8
Figure 8
The binding mode of 14 [76] in MMP-12 catalytic domain (PDB: 5I0L). Image generated with Chimera, version 1.13.
Figure 9
Figure 9
Chemical structure of hyaluronic acid-based MMP-2 inhibitors 26–37.
Figure 10
Figure 10
Chemical structure of DNJ, Miglitol and Zavesca.
Figure 11
Figure 11
Chemical structure of azasugar-based MMP/ADAM inhibitors (Series 1–4).
Figure 12
Figure 12
Chemical structure of azasugar-based TACE inhibitors (54–58).
See this image and copyright information in PMC

References

    1. Bode W., Gomis-Rüth F.-X., Stöckler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’. FEBS Lett. 1993;331:134–140. doi: 10.1016/0014-5793(93)80312-I. - DOI - PubMed
    1. Tallant C., García-Castellanos R., Baumann U., Gomis-Rüth F.X. On the Relevance of the Met-turn Methionine in Metzincins. J. Biol. Chem. 2010;285:13951–13957. doi: 10.1074/jbc.M109.083378. - DOI - PMC - PubMed
    1. Vandenbroucke R.E., Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat. Rev. Drug Discov. 2014;13:904–927. doi: 10.1038/nrd4390. - DOI - PubMed
    1. Murphy G., Nagase H. Progress in matrix metalloproteinase research. Mol. Asp. Med. 2008;29:290–308. doi: 10.1016/j.mam.2008.05.002. - DOI - PMC - PubMed
    1. Maskos K. Crystal structures of MMPs in complex with physiological and pharmacological inhibitors. Biochimie. 2005;87:249–263. doi: 10.1016/j.biochi.2004.11.019. - DOI - PubMed

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