Inhibition of stromelysin-1 (MMP-3) by peptidyl phosphinic acids

Goulet, Joung L.; Kinneary, Joanne F.; Durette, Philippe L.; Stein, Ross L.; Harrison, Richard K.; Izquierdo-Martin, Maria; Kuo, David; Lin, Tao

doi:10.1016/s0960-894x(01)80334-6

Cited by 31 publications

(22 citation statements)

References 11 publications

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“…However, as only relatively long peptides seem to act as good substrates of MMP-9, longer sequences might be necessary in order to prepare potent inhibitors. This phenomenon was reported for MMP-3, [28] where the elongation of the P 3 subsite of a phosphinic peptide increased the affinity.…”

Section: Introductionsupporting

confidence: 63%

“…[36] By coordinating to zinc, the oxy-anion of phosphinic acids mimics the unstable tetrahedral transition state of the peptide bond cleavage site, a feature which is crucial to their function as inhibitors. [27,36] The phosphinic moiety has been utilized for the construction of many inhibitors of a variety of enzymes such as MMP-3, [28,35] collagenases, [25,37,38] other zinc metalloproteases, [22, 26, 27, 39±41] HIV-protease, [42,43] other aspartic proteases, [32,44,45] ligases, [23,24,46,47] and yet other enzymes.…”

Section: Introductionmentioning

confidence: 99%

“…[48±50] Phosphinic peptides have been prepared both in solution [27,28,37,44] and more recently on the solid phase. [22,39,40, 51±53] The solid-phase synthesis technique [54] has a number of advantages in the synthesis of sequential oligomeric molecules.…”

Section: Introductionmentioning

confidence: 99%

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Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

et al. 1999

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The solid-phase synthesis of an array of different pseudopeptides containing a phosphinic glycine ± leucine moiety (-GY{P(O)OH-CH 2 }L-) [1] is described. The resulting pseudopeptides were shown to act as matrix metalloproteinase-9 (MMP-9) inhibitors. Starting from available materials, the protected amino acid isosters benzyloxycarbonyl aminomethylphosphinic acid (glycine analogue) and ethyl a-isobutylacrylate (leucine analogue) were synthesized and coupled with the bis(trimethylsilyl)phosphonite. Protective group interchange yielded a protected phosphinic dipeptide building block 1 ready for use in solid-phase peptide synthesis. Solid-phase peptide synthesis was performed with 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry on a polyethylene glycol polyamide (PEGA) support and the coupling of 1 (1.5 equiv) was carried out with standard activation. The P 4 ± P 2 and P 2 ' ± P 4 ' positions of the pseudopeptides were designed by analogy of the cleavage sequences of different natural extracellular matrix protein substrates with a synthetic peptide substrate of MMP-9. The crude peptides were obtained in high yield and purity as determined by RP-HPLC, and were characterized by electrospray mass spectrometry and amino acid analysis after purification. Enzyme kinetic investigations with MMP-9 of the purified peptide inhibitors showed K i values in the range from mm to nm.

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Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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Phosphinic Peptide Matrix Metalloproteinase-9 Inhibitors by Solid-Phase Synthesis Using a Building Block Approach

et al. 1999

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“…This view is consistent with the very good potency displayed by phosphinic peptides towards several zinc proteinases, [66][67][68] and MMPs in particular. [69][70][71][72][73] Finally, as compared to many other class of zinc protease inhibitors, phosphinic peptide chemistry offers the possibility of developing inhibitors able to interact with both the primed and unprimed side of the active-site cleft, allowing optimization of inhibitor selectivity by diversification of both P and P 0 positions of the inhibitors. As far as the synthesis of the phosphinic pseudodipeptidic blocks is of concern, numerous synthetic strategies have been developed and reviewed, 74,75 including building block approaches [76][77][78][79] or post-modification of phosphinopeptidic precursors.…”

Section: D E S I G N a N D D E V E L O P M E N T O F S E L E C T I mentioning

confidence: 99%

Matrix metalloproteinase 11 (MMP‐11; stromelysin‐3) and synthetic inhibitors

Matziari

Dive

Yiotakis

2006

Medicinal Research Reviews

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Matrix metalloproteinase (MMP)-11, or Stromelysin 3, is a particular member of MMP family, a group of zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling. Despite intense efforts since its first characterization 15 years ago, its role and target substrates in different diseases remain largely unknown. While mice with MMP-11 deficiency display no particular phenotype, analysis of different tumorigenesis models with these mice lead to the conclusion that MMP-11 promotes tumor development. In contrast with other MMPs, MMP-11 is unable to degrade any major extracellular matrix component and unlike most of other MMPs that are secreted as inactive proenzymes and activated extracellularly, MMP-11 is secreted under active form. MMP-11 may thus play a unique role in tissue remodeling processes, including those associated with tumor progression. Although MMP-11 and other MMPs have been considered as promising targets to combat cancer, a first series of clinical trials using broad-spectrum MMP inhibitors have not led to significant therapeutic benefits. These disappointing results highlight the need for better understanding of the exact role played by each MMP during the different stages of tumor progression. Among the different strategies to fill this gap, highly specific MMP inhibitors would be of great value. This review provides an update on the selectivity profile of phosphinic MMP-11 synthetic inhibitors developed and discusses the opportunities and limitations to identify inhibitors able to fully discriminate MMP-11 from the other MMPs.

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“…They have shown that potent [ ( _ ) T D $ F I G ] and selective inhibition of MMP-3 with these peptidylphosphinic acids requires extension of substitution into the P3 position. Thus, compound 12 was found to be approximately 500 fold more potent against MMP-3 vs. MMP-1 [46]. In a later paper from the same laboratory, it has been shown that phosphonic acid 13a inhibited MMP-3 more effectively than the corresponding phosphonamidate and phosphonate analogs.…”

Section: Phosphinic Acidsmentioning

confidence: 94%