Detection of Endogenous Matrix Metalloprotease-12 Active Form with a Novel Broad Spectrum Activity-based Probe*

Abstract

Background:The detection of MMP active forms remains a challenge. Results: An endogenous active form of MMP-12 was detected in animal fluids with a new activity-based probe. Conclusion:The presence of MMP active forms can be demonstrated only with a highly sensitive probe. Significance: It should be possible to validate active forms of MMP as potential biomarkers in different physiopathological contexts.

Ligand‐Directed Modification of Active Matrix Metalloproteases: Activity‐based Probes with no Photolabile Group

“…Alternatively, the NASA linker may be repositioned along the pseudo‐peptide backbone to target other lysine residues present in the hMMP12 catalytic cleft. Overall, the labelling performances of RXP470.1‐derived probes 1 and 2 in complex proteomes remain comparable to those previously reported in the literature for photolabile activity‐based probes targeting MMPs [16, 17, 25, 43] …”

“…Overall, the labelling performances of RXP470.1-derived probes 1 and 2 in complex proteomes remain comparable to those previously reported in the literature for photolabile activity-based probes targeting MMPs. [16,17,25,43] In the perspective of using RXP470.1-derived probes in biological samples collected from preclinical mice models or in vivo,the reactivity of probe 2 towards recombinant mouse MMP-12 (rmMMP-12) was investigated. At pH 7.5, the labelling of rmMMP-12 (40 nM) was validated but required 300 nM of probe 2 to be as efficient as that of rhMMP-12 by the same probe used at 100 nM (Figure S6B).…”

Matrix Metalloproteinases as New Targets in Alzheimer’s Disease: Opportunities and Challenges

“…Devel et al designed the highly potent and selective MMP-12 phosphinic inhibitor 12 (also called RXP470.1) by introducing an isoxazole side chain to fill the S1′ cavity as well as a Glu-Glu motif to occupy S2′ and S3′ subsites (Figure C). , An interesting study on this compound revealed the crucial and complex role of the ZBG to modulate either the potency, dynamics, or selectivity of the inhibitor . The same group then developed a new generation of nonphosphinic pseudopeptides with modified P1′ side chains, like compound 13 (Figure C), which were even more selective than 12 . , In addition to their potential interest as therapeutic agents, some peptidomimetics could be used as probes and pharmacological or diagnostic tools in cellulo or in preclinical models …”

“…191,192 In addition to their potential interest as therapeutic agents, some peptidomimetics could be used as probes and pharmacological or diagnostic tools in cellulo or in preclinical models. 193 Another example of selective inhibitor is the intriguing synthetic APP-IP decapeptide 14 that interacts with the catalytic site of MMP-2 (Figure 10C). As discussed above, the sequence of APP-IP corresponds to an internal sequence of APP (residues 586−595, APP 770 numbering) that was identified as the minimal region required for MMP-2 10C).…”

Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology

“…Compared with the phenyl azido probes, such a probe reacted efficiently with a larger set of MMPs and was able to detect endogenous MMP12 in bronchoalveolar lavage fluids (Nury et al, 2013a). More widely, ABPs targeting the S 1 ' subsite are more effective than those targeting the S 2 ' and S 3 ' subsites.…”