Inhibition of procollagen C-proteinase: fibrosis and beyond

  title={Inhibition of procollagen C-proteinase: fibrosis and beyond},
  author={Eric D. Turtle and Wen-Bin Ho},
  journal={Expert Opinion on Therapeutic Patents},
  pages={1185 - 1197}
  • E. Turtle, W. Ho
  • Published 1 August 2004
  • Biology, Medicine
  • Expert Opinion on Therapeutic Patents
Procollagen C-proteinase (PCP) plays a key role in fibrosis. The activity of PCP is necessary to convert soluble procollagens into fully formed collagen fibrils. Fibrosis is a pathological condition in which the normal wound healing process goes awry, culminating in the excessive production and deposition of collagen, a major component of scar tissue. The persistent formation of scar tissue hinders proper tissue function and can lead to organ failure in a wide range of fibrotic diseases. PCP is… 

Design and synthesis of procollagen C-proteinase inhibitors.

Procollagen C-proteinase Enhancer Stimulates Procollagen Processing by Binding to the C-propeptide Region Only*

A detailed quantitative study of the binding of PCPE-1 and of its minimal active fragment (CUB1-CUB2) to three regions of the procollagen III molecule: the triple helix, the C-telopeptide, and the C,propeptide.

Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.

Structural-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases, and a novel class of reverse hydroxamate BMP1 inhibitors was discovered.

BMP1 is not required for lung fibrosis in mice

It is proposed that B MP1 is not required for lung fibrosis in mice and BMP1 may not be considered a candidate therapeutic target for IPF.

Inhibitors of BMP‐1/tolloid‐like proteinases: efficacy, selectivity and cellular toxicity

It is found that hydroxamate FG‐2575 and the protein sizzled are very powerful and selective inhibitors of BMP‐1, whereas phosphinic peptide RXP‐1001 behaves as a broad‐spectrum inhibitor of astacins.

Dynamics of the secreted frizzled related protein Sizzled and potential implications for binding to bone morphogenetic protein-1 (BMP-1)

A new crystal structure for Szl is presented which differs from that previously reported by a large scale hinge rotation between its cysteine-rich and netrin-like domains and reveals features that may be helpful in the design of new inhibitors to prevent the excessive accumulation of extracellular matrix that is the hallmark of fibrotic diseases.

Using a peptide-based mass spectrometry approach to quantitate proteolysis of an intact heterogeneous procollagen substrate by BMP1 for antagonistic antibody screening

A peptide-based in vitro functional screening assay for antibody inhibitors of mouse bone morphogenic protein 1 (mBMP1) metalloprotease using a heterogeneous recombinant 66-kDa mouse Procollagen I alpha 1 chain (mProcollagen) substrate was established and was concluded to be the most suitable approach in terms of throughput, sensitivity, and assay robustness.



Design and synthesis of acidic dipeptide hydroxamate inhibitors of procollagen C‐proteinase

  • A. OvensJ. JouleK. Kadler
  • Biology, Chemistry
    Journal of peptide science : an official publication of the European Peptide Society
  • 2000
The design and synthesis of acidic side chain hydroxamate dipeptide inhibitors of PCP having IC50 values in the range 0.1–10 μm that mimic the location of aspartic acid residues in the P1′ and P2′ positions of the PCP cleavage site in procollagen are described.

Procollagen peptidase: an enzyme excising the coordination peptides of procollagen.

The enzyme activity is absent in dermatosparaxic connective tissues, thus suggesting that dermatosParaxis is caused by the absence of a normal enzyme function rather than by the production of an abnormal collagen.

Bone Morphogenetic Protein-1: The Type I Procollagen C-Proteinase

This demonstration of enzymatic activity for a BMP-1/TLD-like protein links an enzyme involved in matrix deposition to genes involved in pattern formation in vertebrate extracellular matrix.

Interaction Properties of the Procollagen C-proteinase Enhancer Protein Shed Light on the Mechanism of Stimulation of BMP-1*

PN-collagen (i.e.procollagen devoid of the C-terminal propeptide domain) was found to bind to immobilized PCPE, suggesting that PCPE binds to sites on either side of the procollagen cleavage site, thereby facilitating the action of Procollagen C-proteinases.

Proteinases of the Bone Morphogenetic Protein-1 Family Convert Procollagen VII to Mature Anchoring Fibril Collagen*

It is shown that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from humanprocollagen VII, and that Mammalian tolloid-like (mTLL)-1 and -2, two other proteases of the astacin enzyme family, were able to process procollage VII at the same site in vitro.

Novel inhibitors of procollagen C-proteinase. Part 2: glutamic acid hydroxamates.

The C-proteinase that processes procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-1.

It is demonstrated that procollagen C-proteinase is identical to BMP-1, a member of the "astacin families" of zinc-requiring endopeptidases that play critical roles in embryonic hatching, dorsal/ventral patterning, and early developmental decisions.

Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases

Findings raise the possibility that members of the BMP-1/TLD family may be involved in activating latent myostatin in vivo and that molecules capable of inhibiting these proteinases may be effective agents for increasing muscle mass for both human therapeutic and agricultural applications.