Specificity of Binding with Matrix Metalloproteinases

Gupta, Satya P.; Patil, Vaishali M.

doi:10.1007/978-3-0348-0364-9_2

Cited by 41 publications

(44 citation statements)

References 77 publications

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“…7, Table II). Neutrophil granules contain two soluble metalloproteinases, MMP-8 and MMP-9 (59,60). Similar to our observation that MMP-8 degrades LLO (Fig.…”

Section: Discussionsupporting

confidence: 91%

“…Human neutrophils produce three metalloproteinases: MMP-8 (collagenase), MMP-9 (gelatinase), and MMP-25 (leukolysin or MT6-MMP). The first two are soluble and membrane-associated, whereas MMP-25 is only membraneassociated (59,60). We determined if commercially available, purified MMP-8 and/or MMP-9 could degrade LLO.…”

Section: A Metalloproteinase Is Responsible For Llo Inhibitionmentioning

confidence: 99%

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The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils

Arnett

Vadia

Nackerman

et al. 2014

The Journal of Immunology

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The pore-forming toxin listeriolysin O (LLO) is a major virulence factor secreted by the facultative intracellular pathogen Listeria monocytogenes. This toxin facilitates L. monocytogenes intracellular survival in macrophages and diverse nonphagocytic cells by disrupting the internalization vesicle, releasing the bacterium into its replicative niche, the cytosol. Neutrophils are innate immune cells that play an important role in the control of infections, yet it was unknown if LLO could confer a survival advantage to L. monocytogenes in neutrophils. We report that LLO can enhance the phagocytic efficiency of human neutrophils and is unable to protect L. monocytogenes from intracellular killing. To explain the absence of L. monocytogenes survival in neutrophils, we hypothesized that neutrophil degranulation leads to the release of LLO-neutralizing molecules in the forming phagosome. In support of this, L. monocytogenes is a potent inducer of neutrophil degranulation, since its virulence factors, such as LLO, facilitate granule exocytosis. Within the first few minutes of interaction with L. monocytogenes, granules can fuse with the plasma membrane at the bacterial interaction site before closure of the phagosome. Furthermore, granule products directly degrade LLO, irreversibly inhibiting its activity. The matrix metalloproteinase-8, stored in secondary granules, was identified as an endoprotease that degrades LLO, and blocking neutrophil proteases increased L. monocytogenes intracellular survival. In conclusion, we propose that LLO degradation by matrix metalloproteinase-8 during phagocytosis protects neutrophil membranes from perforation and contributes to maintaining L. monocytogenes in a bactericidal phagosome from which it cannot escape.

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“…7, Table II). Neutrophil granules contain two soluble metalloproteinases, MMP-8 and MMP-9 (59,60). Similar to our observation that MMP-8 degrades LLO (Fig.…”

Section: Discussionsupporting

confidence: 91%

Section: A Metalloproteinase Is Responsible For Llo Inhibitionmentioning

confidence: 99%

The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils

Arnett

Vadia

Nackerman

et al. 2014

The Journal of Immunology

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“…Eight residue positions (T190, F198, Y203, F204, N229, N231, S251, and F260) were selected for Ala substitution, based on the following criteria: (i) distinct in MMP-14 relative to MMP-2 and MMP-9 (Fig. S8A), (ii) within a distance of 15 Å from the catalytic Zn 2+ , (iii) exhibiting an exposed respective side chain, and (iv) near the S1′ subsite (40,41). The resulting MMP-14 mutants were expressed in the periplasmic space of E. coli (42).…”

Section: Significancementioning

confidence: 99%

Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries

Nam

Rodríguez

Remacle

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

110

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Proteases are frequent pharmacological targets, and their inhibitors are valuable drugs in multiple pathologies. The catalytic mechanism and the active-site fold, however, are largely conserved among the protease classes, making the development of the selective inhibitors exceedingly challenging. In our departure from the conventional strategies, we reviewed the structure of known camelid inhibitory antibodies, which block enzyme activities via their unusually long, convex-shaped paratopes. We synthesized the human Fab antibody library (over 1.25 × 10 9 individual variants) that carried the extended, 23-to 27-residue, complementarity-determining region (CDR)-H3 segments. As a proof of principle, we used the catalytic domain of matrix metalloproteinase-14 (MMP-14), a promalignant protease and a drug target in cancer, as bait. In our screens, we identified 20 binders, of which 14 performed as potent and selective inhibitors of MMP-14 rather than as broad-specificity antagonists. Specifically, Fab 3A2 bound to MMP-14 in the vicinity of the active pocket with a high 4.8 nM affinity and was similarly efficient (9.7 nM) in inhibiting the protease cleavage activity. We suggest that the convex paratope antibody libraries described here could be readily generalized to facilitate the design of the antibody inhibitors to many additional enzymes. family members control various physiological and pathological processes. Multiple diseases are associated with altered MMP expression and aberrant proteolysis, including cancer (1), wound healing (2), inflammatory diseases (3, 4), neurological pain (5, 6), and hypertension (7). There is consensus among researchers that the individual MMPs are promising drug targets in diversified pathologies and that inhibitor specificity is required for selective and successful MMP therapies (8-10).However, achieving target specificity and selectivity in small-molecule MMP inhibitors is remarkably challenging (11,12). Because the catalytic mechanism and catalytic domain fold are conserved among the MMP/ADAM (a disintegrin and metalloproteinase)/ ADAMTS (ADAM with thrombospondin motifs) superfamily members, the available small-molecule inhibitors (most frequently, active-site zinc-chelating hydroxamates) target multiple proteinases, resulting in off-target side effects (8,(12)(13)(14). This aspect is problematic, given that some MMPs (e.g., MMP-14) are always protumorigenic, whereas some other MMPs are antitumorigenic in certain cancer microenvironments (15, 16). As a result, broad-spectrum hydroxamates failed in cancer clinical trials due to their low overall efficacy and side effects (13). Alternatively, antibody-based MMP inhibitors are emerging as both research tools and potential therapeutic agents (10, 17-21) because of (i) high affinity and specificity due to the large antigen-antibody interaction area and multiple complementarity-determining regions (CDRs), (ii) long half-life and well-defined action mechanisms, (iii) low immunogenicity and toxicity, and (iv) multiple MMPs potentially targe...

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“…They are controlled by hormones, growth factors and cytokines and are excreted by a variety of tissue and pro-inflammatory cells, i.e., fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, lymphocytes [15]. So far 28 types of human matrix metalloproteinases have been recognized and been classified as collagenases, gelatinases, stromelysins, matrilysins, membraneType [16]. Researches of MI have showed increased levels of several MMPs.…”

Section: Novel Markersmentioning

confidence: 99%

Left Ventricular Remodeling after Acute Myocardial Infarction and Biomarkers

Žaliaduonytė-Pekšienė¹,

Portacenko²

2017

J Cardiovasc Dis Diagn

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Considering to pathogenetic mechanisms of MI a few classical biomarkers have been used for diagnosis of MI or acute coronary syndrome. Lately novel markers have been identified to provide diagnostic and prognostic information and outcome of MI or acute coronary syndrome. A few novel biomarkers are overviewed in this article. A few novel biomarkers mentioned in this article showed significant relation to left ventricle remodelling and poor prognosis after myocardial infarction.

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Specificity of Binding with Matrix Metalloproteinases

Cited by 41 publications

References 77 publications

The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils

The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils

Active-site MMP-selective antibody inhibitors discovered from convex paratope synthetic libraries

Left Ventricular Remodeling after Acute Myocardial Infarction and Biomarkers

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