Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase

Fish, Paul V.; Allan, Gill; Bailey, Simon; Blagg, Julian; Butt, Richard P.; Collis, Michael G.; Greiling, Doris; James, K.; Kendall, Jackie D.; McElroy, Andrew B.; McCleverty, D.; Reed, Charlotte; Webster, Robert O.; Whitlock, Gavin A.

doi:10.1021/jm061010z

Cited by 65 publications

(64 citation statements)

References 21 publications

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“…The inhibitor used was 5-((R)-4-cyclohexyl-1-hydroxycarbamoylmethyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid amide, corresponding to compound 1 in Ref. 23. A titration experiment using the same inhibitor showed that it binds in a 1:1 ratio with BMP-1, in keeping with the enzymatic active site titration data (Fig.…”

Section: Characterization Of Bmp-1 By Nmrsupporting

confidence: 58%

Structural Basis for the Substrate Specificity of Bone Morphogenetic Protein 1/Tolloid-like Metalloproteases

Sweeney

Gil-Parrado

Vinzenz

et al. 2008

Journal of Molecular Biology

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Section: Characterization Of Bmp-1 By Nmrsupporting

confidence: 58%

Structural Basis for the Substrate Specificity of Bone Morphogenetic Protein 1/Tolloid-like Metalloproteases

Sweeney

Gil-Parrado

Vinzenz

et al. 2008

Journal of Molecular Biology

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“…Based on this observation, we postulate that such a reduction could offer an additional mechanism for reducing formation of fibrillar deposits. The idea of blocking BMP-1 to limit fibrosis was suggested by others, and a number of inhibitors of BMP-1 have been developed and tested as potential inhibitors of fibrosis (36). At the same time, however, it has been demonstrated that, in addition to procollagen I, BMP-1 cleaves other substrates and that its activity is critical for a number of processes not related to fibrosis (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Collagen Fibril Formation

Chung

Steplewski

Chung

et al. 2008

Journal of Biological Chemistry

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We present a concept for reducing formation of fibrotic deposits by inhibiting self-assembly of collagen molecules into fibrils, a main component of fibrotic lesions. Employing monoclonal antibodies that bind to the telopeptide region of a collagen molecule, we found that blocking telopeptide-mediated collagen/collagen interactions reduces the amount of collagen fibrils accumulated in vitro and in keloid-like organotypic constructs. We conclude that inhibiting extracellular steps of the fibrotic process provides a novel approach to limit fibrosis in a number of tissues and organs.Collagen I is the most abundant structural protein of connective tissues such as skin, bone, and tendon. This protein is first synthesized as a precursor molecule, procollagen, that is characterized by the presence of a rod-like central triple-helical domain flanked by short linear telopeptides and globular N-terminal and C-terminal propeptides (1). Single procollagen molecules are the building blocks for the biologically and mechanically relevant collagen fibrils. Formation of collagen fibrils is initiated by enzymatic cleavage of the N-terminal and the C-terminal propeptides. The N-terminal propeptides are cleaved by a group of enzymes that includes a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-2, -3, and -14, whereas the C-terminal propeptides are cleaved by the metalloprotease bone morphogenetic protein 1 (BMP-1) 2 and by the other members of a closely related family of mammalian tolloid-like metalloproteases (2-4). Such a removal of procollagen propeptides exposes telopeptides, which by engaging in site-specific intermolecular interactions drive collagen self-assembly.In native tissues a precise balance between the processes of biosynthesis and degradation maintains the physiological homeostasis of tissue collagens. At the same time, accelerated biosynthesis is required for proper wound healing, whereas excessive accumulation of collagen is the hallmark of a number of localized fibrotic diseases, such as keloids and hypertrophic scars, and systemic fibrosis, such as systemic scleroderma.Localized fibrotic reactions are quite common and frequently develop as a consequence of surgical procedures. For instance, after surgery of the abdomen, the formation of excessive scar tissue around abdominal organs, such as the intestines, can interfere with the functionality of such organs and may cause severe pain and even death. Another situation where excessive scar formation presents a major complication is in the eye after glaucoma surgery performed to create a pressuremaintenance valve. Frequently, however, excessive scar formation closes this pressure-reducing valve, thereby forcing the intraocular pressure to rise (5). Moreover, excessive scarring of the vocal folds may severely alter their ability to vibrate, thereby causing a number of voice disorders (6).At present, several biological processes critical for development of fibrotic lesions are considered potential targets for inhibitors of fibrosis. These inhibit...

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“…Prior studies have demonstrated that direct modification of these biochemical signals results in reduced adult skin scarring. [87][88][89][90][91][92] For example, neutralization of TGF-b1/2 and/or addition of TGF-b3, 88 downregulation of connexin 43 (Cx43) protein levels, 89 and exogenous application of angiotensin peptides 87 have all been shown to reduce scar formation in adult skin. However, these studies are validated primarily in animal models.…”

Section: Mechanomodulation and Emerging Mechanotherapiesmentioning

confidence: 99%

Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation

Barnes

Marshall

Leavitt

et al. 2018

Advances in Wound Care

171

131

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Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.

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Potent and Selective Nonpeptidic Inhibitors of Procollagen C-Proteinase

Cited by 65 publications

References 21 publications

Structural Basis for the Substrate Specificity of Bone Morphogenetic Protein 1/Tolloid-like Metalloproteases

Structural Basis for the Substrate Specificity of Bone Morphogenetic Protein 1/Tolloid-like Metalloproteases

Collagen Fibril Formation

Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation

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