Recent advances in matrix metalloproteinase inhibitor research

Becket, R P; Davidson, Alan H.; Drummond, Alan H.; Huxley, P; Whittaker, Mark

doi:10.1016/1359-6446(96)89115-x

Cited by 266 publications

(187 citation statements)

References 66 publications

Supporting

Mentioning

177

Contrasting

Unclassified

Order By: Relevance

“…Based on the fact that both reagents are distinct but highly effective inhibitors of MMP activity 27,45 and that natural inhibitors like the TIMPs have no known toxic or side effects, the most logical explanation for their similar inhibitory effects on angiogenesis is that they block MMP-mediated proteolysis. However, because BB-3103 and TIMP-1 can both block a broad range of MMPs, 45,46 we cannot directly predict from these data which specific enzymes are the relevant targets in the observed inhibition of blood vessel growth. Selective inhibitors of individual MMPs are not yet available.…”

Section: Discussionmentioning

confidence: 99%

Growth factor–induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen

Seandel

Noack-Kunnmann

Zhu

et al. 2001

Blood

137

120

View full text Add to dashboard Cite

The contribution of specific type I collagen remodeling in angiogenesis was studied in vivo using a quantitative chick embryo assay that measures new blood vessel growth into well-defined fibrillar collagen implants. In response to a combination of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), a strong angiogenic response was observed, coincident with invasion into the collagen implants of activated fibroblasts, monocytes, heterophils, and endothelial cells. The angiogenic effect was highly dependent on matrix metalloproteinase (MMP) activity, because new vessel growth was inhibited by both a synthetic MMP inhibitor, BB3103, and a natural MMP inhibitor, TIMP-1. Multiple MMPs were detected in the angiogenic tissue including MMP-2, MMP-13, MMP-16, and a recently cloned MMP-9-like gelatinase. Using this assay system, wild-type collagen was compared to a unique collagenase-resistant collagen (r/r), with regard to the ability of the respective collagen implants to support cell invasion and angiogenesis. It was found that collagenase-resistant collagen constitutes a defective substratum for angiogenesis. In implants made with r/r collagen there was a substantial reduction in the number of endothelial cells and newly formed vessels. The presence of the r/r collagen, however, did not reduce the entry into the implants of other cell types, that is, activated fibroblasts and leukocytes. These results indicate that fibrillar collagen cleavage at collagenase-specific sites is a ratelimiting event in growth factor-stimulated angiogenesis in vivo. IntroductionAngiogenesis is the process by which the preexisting vascular tree gives rise to new blood vessels. This process is tightly regulated during development and occurs only under highly specialized circumstances in the normal adult animal. Unregulated angiogenesis may be a pivotal element of disease etiology, such as during tumor growth and atherosclerosis. 1,2 All forms of angiogenesis, however, are thought to share certain basic features, including migration and mitogenesis of endothelial cells, lumen formation, connection of new vascular segments with the preexisting circulation, and extensive remodeling of the extracellular matrix by proteases. The detailed mechanisms by which proteolytic enzymes, such as the matrix metalloproteinases (MMPs), mediate some of these events in vivo remain unclear. 3,4 The MMPs constitute a large family of zinc-dependent endopeptidases that have been strongly implicated in both normal angiogenesis and tumor vascularization. 2,4 These enzymes are characteristically regulated at multiple levels, including gene expression, spatial localization, zymogen activation, and inhibition by the tissue inhibitors of metalloproteinases (TIMPs). 5 In vitro remodeling of extracellular matrices by cultured endothelial cells has consistently been shown to rely on MMPs. 4 However, it is unclear which aspects of cell culture models for angiogenesis may be directly extrapolated to the animal. In vivo studies also have foun...

show abstract

Section: Discussionmentioning

confidence: 99%

Growth factor–induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen

Seandel

Noack-Kunnmann

Zhu

et al. 2001

Blood

137

120

View full text Add to dashboard Cite

show abstract

“…In the present study we have provided the first detailed structure-activity relationship for inhibition of the ACE secretase by examining the effect of representative members of the matrix metalloprotease inhibitors, particularly those of the hydroxamic acid class. The most potent inhibitors of ACE secretase from these various classes, all of which are known inhibitors of collagenase [23][24][25][26], were the hydroxamates batimastat, TAPI-2 and compound 6, which elicited IC &! values in the low micromolar range.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme secretase is inhibited by zinc metalloprotease inhibitors and requires its substrate to be inserted in a lipid bilayer

Parvathy

Oppong

Karran

et al. 1997

Biochemical Journal

View full text Add to dashboard Cite

Mammalian angiotensin-converting enzyme (ACE ; EC 3.4.15.1) is one of several proteins that exist in both membrane-bound and soluble forms as a result of a post-translational proteolytic processing event. For ACE we have previously identified a metalloprotease (secretase) responsible for this proteolytic cleavage. The effect of a range of structurally related zinc metalloprotease inhibitors on the activity of the secretase has been examined. Batimastat (BB94) was the most potent inhibitor of the secretase in pig kidney microvillar membranes, displaying an IC &! of 0.47 µM, whereas TAPI-2 was slightly less potent (IC &! 18 µM). Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2h substituent decreased the inhibitory potency of batimastat towards the secretase. Several other non-hydroxamate-based collagenase inhibitors were without inhibitory effect on the secretase, indicating that ACE secretase is a novel zinc metalloprotease that is related to, but distinct from, the matrix metalloproteases. The full-length amphipathic form of ACE was labelled selectively

show abstract

“…Because gelatinases are thought to play an important role in triggering the processes of tumor growth, invasion, and metastasis by cleaving the vascular basement membrane that consists of type IV collagen, gelatinase inhibitors have been studied extensively in the search for a new type of anticancer drug. 28,29 The recent resolution of the crystal structure of MMP-2 provides the opportunity to develop new drugs by the structure-based approach. 30 Many MMP inhibitors have been reported.…”

Section: Introductionmentioning

confidence: 99%

Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models

Hou

Guo

2002

J. Phys. Chem. B

View full text Add to dashboard Cite

The free energies of binding, ∆G bind , between a diverse set of eight hydroxamate inhibitors with gelatinase-A (MMP-2) were computed by using the recently developed MM/PBSA approach. In this paper, a nonbonded model was used to represent the potentials of the catalytic zinc center. Molecular dynamics (MD) simulations were used to generate the thermally averaged ensemble of conformations of the ligand-protein complexes. On the basis of the trajectories from MD simulations, the free energies of binding were calculated using molecular mechanics, the continuum solvent model, surface area estimation, and normal-mode analysis. The results show that MM/PBSA not only can rank the studied ligands effectively but also can reproduce the experimental binding free energies successfully. The predicted binding free energies correlate well with the experimental values (r ) 0.84, q ) 0.78). As a comparison, the free energies of binding were also computed by using the linear interaction energy approximation (LIE). The overall agreement between the calculated and experimental values for the diverse set of ligands means that the MM/PBSA approach is a useful tool for the general evaluation of protein-ligand interactions. The analysis of the separate energy terms contributing to MM/PBSA free energy indicates that the association between hydroxamate and MMP-2 is mainly driven by more favorable van der Waals/nonpolar interactions in the complex than in solution.

show abstract

Recent advances in matrix metalloproteinase inhibitor research

Cited by 266 publications

References 66 publications

Growth factor–induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen

Growth factor–induced angiogenesis in vivo requires specific cleavage of fibrillar type I collagen

Angiotensin-converting enzyme secretase is inhibited by zinc metalloprotease inhibitors and requires its substrate to be inserted in a lipid bilayer

Predictions of Binding of a Diverse Set of Ligands to Gelatinase-A by a Combination of Molecular Dynamics and Continuum Solvent Models

Contact Info

Product

Resources

About