Issue 42, 2017

Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues

Abstract

“A disintegrin and metalloproteinase 17” (ADAM17), or tumour necrosis factor (TNF)-α converting enzyme, is an upstream target for mitigating TNF-α-mediated inflammation. ADAM17 can be inhibited by chelation of its catalytic site zinc cofactor, which is required for substrate catalysis and structure stabilization. In this study, rye secalin-derived tripeptides (CQV and QCA) and analogues (QCV and QVC) showed zinc-chelating capacity (∼35% at 0.5 μM) and dose-dependently inhibited ADAM17 activity with up to 70% inhibition were observed at 5 μM. Moreover, ADAM17 intrinsic fluorescence emission was quenched by the peptides via the dynamic mechanism, with CQV producing the highest quenching constants. Molecular docking revealed that the tripeptides interacted with ADAM17 active site residues, mostly occupying the S1 and S1′ subsites. CQV had the shortest distance to the zinc cofactor and lowest binding energy. The peptides coordinated zinc through their C-terminal carboxylate anions for QCV, QVC and CQV, and peptide bond carbonyl for CQV. CQV also had more hydrogen bonding with the N, O and H atoms of ADAM17 active site residues but, unlike the other peptides, this did not involve the peptidyl sulfhydryl groups. Interaction with ADAM17 S1′ hydrophobic pockets suggests a possible selectivity of the peptides for ADAM17. Despite their promise as bioactive candidates for controlling inflammation, incubation of THP-1 human monocytic cells with the tripeptide at a concentration that inhibited ADAM17 activity did not result in inhibition of lipopolysaccharide-stimulated TNF-α release.

Graphical abstract: Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues

Article information

Article type
Paper
Submitted
11 Nov 2016
Accepted
16 Apr 2017
First published
17 May 2017
This article is Open Access
Creative Commons BY license

RSC Adv., 2017,7, 26361-26369

Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues

M. C. Udechukwu, A. Tsopmo, H. Mawhinney, R. He, P. C. Kienesberger and C. C. Udenigwe, RSC Adv., 2017, 7, 26361 DOI: 10.1039/C6RA26678A

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