Synthetic active site-directed inhibitors of metzincins: Achievement and perspectives

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.

Section: Discussionmentioning

confidence: 99%

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

Nury

Bregant

Czarny

et al. 2013

“…In addition, small molecule inhibitors of a hydroxamate class are also readily available for the MMP/ ADAM studies in vitro and in cell-based tests (53)(54)(55)(56). These hydroxamates chelate the active site zinc atom and inactivate MMPs/ADAMs.…”

Section: Inhibitors and Fluorescence-quenched Peptide Substrates Of Mmentioning

confidence: 99%

Substrate Cleavage Profiling Suggests a Distinct Function of Bacteroides fragilis Metalloproteinases (Fragilysin and Metalloproteinase II) at the Microbiome-Inflammation-Cancer Interface

Shiryaev

Remacle

Chernov

et al. 2013

Background: Two distinct metalloproteinase types (fragilysin and metalloproteinase II/MPII) are encoded by the Bacteroides fragilis pathogenicity island. Results: Our assays determined substrate cleavage characteristics of fragilysin and MPII. Conclusion: MPII is the first zinc metalloproteinase with the dibasic cleavage preferences. Significance: Our results are important for understanding B. fragilis virulence and fundamental roles of the microbiome in human health and disease.

“…2 with a variety of pathological states has stimulated impressive efforts over the past 20 years to develop synthetic compounds able to block efficiently (1)(2)(3)(4)(5)(6)(7) and selectively the uncontrolled activity of these enzymes (8). Extremely potent inhibitors of MMPs have been developed, but in most cases these compounds act as broad spectrum inhibitors of MMPs (9).…”

Section: The Association Of Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Insights from Selective Non-phosphinic Inhibitors of MMP-12 Tailored to Fit with an S1′ Loop Canonical Conformation

Devel

Garcia

Czarny

et al. 2010

After the disappointment of clinical trials with early broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs), the field is now resurging with a new focus on the development of selective inhibitors that fully discriminate between different members of the MMP family with several therapeutic applications in perspective. Here, we report a novel class of highly selective MMP-12 inhibitors, without a phosphinic zinc-binding group, designed to plunge deeper into the S 1 cavity of the enzyme. The best inhibitor from this series, identified through a systematic chemical exploration, displays nanomolar potency toward MMP-12 and selectivity factors that range between 2 and 4 orders of magnitude toward a large set of MMPs. Comparison of the high resolution x-ray structures of MMP-12 in free state or bound to this new MMP-12 selective inhibitor reveals that this compound fits deeply within the S 1 specificity cavity, maximizing surface/volume ratios, without perturbing the S 1 loop conformation. This is in contrast with highly selective MMP-13 inhibitors that were shown to select a particular S 1 loop conformation. The search for such compounds that fit precisely to preponderant S 1 loop conformation of a particular MMP may prove to be an alternative effective strategy for developing selective inhibitors of MMPs. The association of matrix metalloproteinases (MMPs)2 with a variety of pathological states has stimulated impressive efforts over the past 20 years to develop synthetic compounds able to block efficiently (1-7) and selectively the uncontrolled activity of these enzymes (8). Extremely potent inhibitors of MMPs have been developed, but in most cases these compounds act as broad spectrum inhibitors of MMPs (9). The arguments that have been proposed to explain the difficulties in identifying inhibitors able to differentiate one MMP from another include: (a) marked sequence similarities between the catalytic domains of MMPs, (b) a well conserved enzyme active site topology (backbone RMSD between the MMP catalytic domains is 0.7-0.8 Å), and (c) the mobility of residues in the so-called S 1 Ј specificity loop (10, 11).MMPs form a group of 23 proteins in humans, all of which contain a catalytic domain belonging to the zinc metalloproteinase family (12, 13). Retrospective analysis suggests that the incorporation of strong zinc-binding groups, such as hydroxamate functions, potentiates MMP inhibition but unfortunately in an indiscriminate manner affecting most members of the MMP family (7), as well as other unrelated zinc-proteinases (14). The use of a less avid zinc-binding group, like the phosphoryl group present in phosphinic peptide transition state analogs, has led to a second generation of more selective MMP inhibitors, like the selective inhibitors reported for MMP-12 (macrophage-metalloelastase) (15). The third generation MMP inhibitors possess no zinc-binding group and exploit mainly the depth of the S 1 Ј cavity present in most MMPs (16,17). This strategy has led to the discovery of the first extre...