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A Phage Display Derived Cyclized Peptide Inhibits Fibrosarcoma Cells Invasion via Suppression of MMP-9 Activity

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Abstract

Matrix metalloproteinases (MMPs) play critical roles in the invasiveness of cancerous cells and metastasis of solid tumors. MMP-9 is a member of this protease family, which is extremely overexpressed in metastatic cells. Here, we described a cyclic peptide which inhibits the MMP-9 activity with high potency. This inhibitor selectively binds to the MMP-9 fibronectin domain and interferes with the interaction of gelatinous substrates with MMP-9, thereby suppressing its gelatinolytic activity. Previously, we isolated and developed a linear peptide, named as RSH-12, from a phage display library which displayed promising results in the inhibition of MMP-9. Next, we decided to improve its biostability via cyclization chemistry and show that RSH-12 has a considerably enhanced stability in human serum. Moreover, the cyclic peptide is still associated with a high potency to inhibit the invasion activity of a human fibrosarcoma cell line. These results demonstrate that the designed cyclic peptide might be considered as a promising therapeutic moiety to target the MMP-9 for the treatment of cancer.

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References

  • Amar S, Fields GB (2015) Potential clinical implications of recent matrix metalloproteinase inhibitor design strategies. Expert Rev Proteomics 12:445–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beaufays J, Lins L, Thomas A, Brasseur R (2012) In silico predictions of 3D structures of linear and cyclic peptides with natural and non-proteinogenic residues. J Pept Sci 18:17–24

    Article  CAS  PubMed  Google Scholar 

  • Bickett DM, Green MD, Berman J et al (1993) A high throughput fluorogenic substrate for interstitial collagenase (MMP-1) and gelatinase (MMP-9). Anal Biochem 212:58–64

    Article  CAS  PubMed  Google Scholar 

  • Bowden ET, Coopman PJ, Mueller SC (2001) Invadopodia: unique methods for measurement of extracellular matrix degradation in vitro. Methods Cell Biol 63:613–627

    Article  CAS  PubMed  Google Scholar 

  • Bruno BJ, Miller GD, Lim CS (2013) Basics and recent advances in peptide and protein drug delivery. Ther Deliv 4:1443–1467

    Article  CAS  PubMed  Google Scholar 

  • Caley MP, Martins VLC, O’Toole EA (2015) Metalloproteinases and wound healing. Adv Wound Care 4:225–234

    Article  Google Scholar 

  • Cardote TAF, Ciulli A (2016) Cyclic and macrocyclic peptides as chemical tools to recognise protein surfaces and probe protein–protein interactions. ChemMedChem 11:787–794

    Article  CAS  PubMed  Google Scholar 

  • Collier IE, Krasnov PA, Strongin AY et al (1992) Alanine scanning mutagenesis and functional analysis of the fibronectin-like collagen-binding domain from human 92-kDa type IV collagenase. J Biol Chem 267:6776–6781

    Article  CAS  PubMed  Google Scholar 

  • Deryugina EI, Quigley JP (2015) Tumor angiogenesis: MMP-mediated induction of intravasation-and metastasis-sustaining neovasculature. Matrix Biol 44:94–112

    Article  PubMed  Google Scholar 

  • Engel CK, Pirard B, Schimanski S et al (2005) Structural basis for the highly selective inhibition of MMP-13. Chem Biol 12:181–189

    Article  CAS  PubMed  Google Scholar 

  • Fields GB (2015) New strategies for targeting matrix metalloproteinases. Matrix Biol 44:239–246

    Article  PubMed  Google Scholar 

  • Fields GB (2019) The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cells 8:984

    Article  CAS  PubMed Central  Google Scholar 

  • Fields GB (2019) Mechanisms of action of novel drugs targeting angiogenesis-promoting matrix metalloproteinases. Front Immunol 10:1278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gang D, Kim DW, Park H-S (2018) Cyclic peptides: promising scaffolds for biopharmaceuticals. Genes (Basel) 9:557

    Article  Google Scholar 

  • Gege C, Bao B, Bluhm H et al (2012) Discovery and evaluation of a non-Zn chelating, selective matrix metalloproteinase 13 (MMP-13) inhibitor for potential intra-articular treatment of osteoarthritis. J Med Chem 55:709–716

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Rabenstein DL (1999) A cleavage cocktail for methionine-containing peptides. J Pept Res 53:548–553

    Article  CAS  PubMed  Google Scholar 

  • Hurd CA, Mott HR, Owen D (2020) Therapeutic peptides targeting the Ras superfamily. Pept Sci 112:e24165

    Article  CAS  Google Scholar 

  • Kim YH, Kwon H-J, Kim D-S (2012) Matrix metalloproteinase 9 (MMP-9)-dependent processing of βig-h3 protein regulates cell migration, invasion, and adhesion. J Biol Chem 287:38957–38969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • La Rocca G, Pucci-Minafra I, Marrazzo A et al (2004) Zymographic detection and clinical correlations of MMP-2 and MMP-9 in breast cancer sera. Br J Cancer 90:1414–1421

    Article  PubMed  PubMed Central  Google Scholar 

  • Li P, Roller PP (2002) Cyclization strategies in peptide derived drug design. Curr Top Med Chem 2:325–341

    Article  CAS  PubMed  Google Scholar 

  • Maupetit J, Derreumaux P, Tufféry P (2010) A fast method for large-scale de novo peptide and miniprotein structure prediction. J Comput Chem 31:726–738

    CAS  PubMed  Google Scholar 

  • Mondal S, Adhikari N, Banerjee S et al (2020) Matrix metalloproteinase-9 (MMP-9) and its inhibitors in cancer: a minireview. Eur J Med Chem 194:112260

    Article  CAS  PubMed  Google Scholar 

  • Ndinguri MW, Bhowmick M, Tokmina-Roszyk D et al (2012) Peptide-based selective inhibitors of matrix metalloproteinase-mediated activities. Molecules 17:14230–14248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirard B (2007) Insight into the structural determinants for selective inhibition of matrix metalloproteinases. Drug Discov Today 12:640–646

    Article  CAS  PubMed  Google Scholar 

  • Raeeszadeh-Sarmazdeh M, Do LD, Hritz BG (2020) Metalloproteinases and their inhibitors: potential for the development of new therapeutics. Cells 9:1313

    Article  CAS  PubMed Central  Google Scholar 

  • Rafferty J, Nagaraj H, McCloskey P et al (2016) Peptide therapeutics and the pharmaceutical industry: barriers encountered translating from the laboratory to patients. Curr Med Chem 23:4231–4259

    Article  CAS  PubMed  Google Scholar 

  • Remacle AG, Golubkov VS, Shiryaev SA et al (2012) Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth. Cancer Res 72:2339–2349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rijkers DTS, den Hartog JAJ, Liskamp RMJ (2002) An optimized solid phase synthesis strategy—including on-resin lactamization—of astressin, its retro‐, inverso‐, and retro–inverso isomers as corticotropin releasing factor antagonists. Biopolymers 63:141–149

    Article  CAS  PubMed  Google Scholar 

  • Roldán V, Marín F, Gimeno JR et al (2008) Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy. Am Heart J 156:85–91

    Article  PubMed  Google Scholar 

  • Scorilas A, Karameris A, Arnogiannaki N et al (2001) Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients. Br J Cancer 84:1488–1496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sela-Passwell N, Rosenblum G, Shoham T, Sagi I (2010) Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition? Biochim Biophys Acta (BBA) 1803:29–38

    Article  CAS  Google Scholar 

  • Shipley JM, Doyle GAR, Fliszar CJ et al (1996) The structural basis for the elastolytic activity of the 92-kDa and 72-kDa gelatinases: role of the fibronectin type II-like repeats. J Biol Chem 271:4335–4341

    Article  CAS  PubMed  Google Scholar 

  • Shoari A, Rasaee MJ, Kanavi MR, Daraei B (2019) Functional mimetic peptide discovery isolated by phage display interacts selectively to fibronectin domain and inhibits gelatinase. J Cell Biochem 120:19699–19711

    Article  CAS  PubMed  Google Scholar 

  • Shoari A, Rasaee MJ, Rezaei Kanavi M et al (2021) In vivo effect of RSH-12, a novel selective mmp-9 inhibitor peptide, in the treatment of experimentally induced dry eye model. Curr Eye Res 46:7–13

    Article  CAS  PubMed  Google Scholar 

  • Tala SR, Schnell SM, Haskell-Luevano C (2015) Microwave-assisted solid-phase synthesis of side-chain to side-chain lactam-bridge cyclic peptides. Bioorg Med Chem Lett 25:5708–5711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thell K, Hellinger R, Schabbauer G, Gruber CW (2014) Immunosuppressive peptides and their therapeutic applications. Drug Discov Today 19:645–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ugarte-Berzal E, Vandooren J, Bailón E et al (2016) Inhibition of MMP-9-dependent degradation of gelatin, but not other MMP-9 substrates, by the MMP-9 hemopexin domain blades 1 and 4. J Biol Chem 291:11751–11760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vandooren J, Van den Steen PE, Opdenakker G (2013) Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol 48:222–272

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Yu YY, Lieu S et al (2013) MMP9 regulates the cellular response to inflammation after skeletal injury. Bone 52:111–119

    Article  PubMed  Google Scholar 

  • Wu C-H, Liu I-J, Lu R-M, Wu H-C (2016) Advancement and applications of peptide phage display technology in biomedical science. J Biomed Sci 23:1–14

    Article  Google Scholar 

  • Zani M-L, Moreau T (2010) Phage display as a powerful tool to engineer protease inhibitors. Biochimie 92:1689–1704

    Article  CAS  PubMed  Google Scholar 

  • Zapico JM, Puckowska A, Filipiak K et al (2015) Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family. Org Biomol Chem 13:142–156

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Alireza Shoari & Mohammad Javad Rasaee

  2. Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran

    Saeed Khalili

  3. Institute for Molecules and Materials, Bio-Organic Chemistry, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands

    Alireza Shoari & Dennis W. P. M. Löwik

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  1. Alireza Shoari
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  2. Saeed Khalili
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  3. Mohammad Javad Rasaee
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  4. Dennis W. P. M. Löwik
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Correspondence to Mohammad Javad Rasaee or Dennis W. P. M. Löwik.

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Shoari, A., Khalili, S., Rasaee, M.J. et al. A Phage Display Derived Cyclized Peptide Inhibits Fibrosarcoma Cells Invasion via Suppression of MMP-9 Activity. Int J Pept Res Ther 28, 136 (2022). https://doi.org/10.1007/s10989-022-10446-6

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