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GKVLAK–(IRIS Blue-(1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid t-butyl ester)-10-acetic acid monoamide))–GGGGTVQQEL.

Authors

Shan L.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2011 Mar 29 [updated 2011 Apr 26].

Excerpt

The fluorescently labeled 16-peptide agent GKVLAK-(IRIS Blue-(1,4,7,10-tetraazacyclododecane-1,4,7-tris(acetic acid t-butyl ester)-10-acetic acid monoamide (DOTAMA)))-GGGGTVQQEL, abbreviated as DCCP16-IRIS Blue, was developed by Tei et al. for optical imaging of the pathological processes associated with high transglutaminase activity (1). Transglutaminases are a family of Ca2+-dependent enzymes that catalyze extracellular covalent cross-linking of proteins (2, 3). These enzymes participate in many important biological processes, such as blood coagulation, skin-barrier formation, hardening of the fertilization envelope, and extracellular matrix assembly (2, 4). They are also involved in multiple pathological processes, including wound healing, cancer, myocardial infarctions, and atherothrombosis (5-7). The fibrin-stabilizing factor XIII (FXIII, also known as plasma transglutaminase) and the tissue transglutaminase (TG2) are the two enzymes that have attracted the greatest interest in transglutaminase-targeted imaging and therapy (1, 8, 9). FXIII cross-links fibrin during blood clotting and subsequently produces a mechanically stronger clot with high fibrinolytic resistance, whereas TG2 catalyzes covalent cross-linking of the extracellular matrix. The enzyme-mediated cross-linking is achieved by forming an isopeptide bond between the γ-carbonyl group of a glutamine (Gln) in one protein and the ε-amino group of a lysine (Lys) residue in a nearby protein (3, 9). This cross-link can be blocked by covalent incorporation of an acyl-acceptor amine substrate into the fibrin units or an acyl-donor Gln-containing peptide complementary to the FXIII-reactive Lys donor cross-linking sites of the protein (1). FXIII and TG2 are much more sensitive toward the Gln-bearing substrates than to amine donor Lys residues. These transglutaminase features form the fundamental basis for the development of imaging agents for detection of transglutaminase activity. In recent years, peptides based either on β-casein and α2-antiplasmin for the Gln-donor substrate requirements or on the bovine αA-crystallin for the amine donor substrate requirements have been synthesized for in vitro transglutaminase assays, and imaging probes consisting of peptides from α2-antiplasmin have been investigated for mapping the activity of endogenous FXIII and TG2 (10-12). Tei et al. designed a new model peptide, DCCP16, which was labeled with Gd for MRI and the fluorescent dye IRIS Blue for optical imaging (1). IRIS Blue is a cyanine dye that has an absorption maximum of 660 nm and an emission maximum of 680 nm in phosphate buffer at pH 7.4. The DCCP16 peptide consists of two moieties. The first moiety is the hexapeptide TVQQEL, which bears two Gln residues and one valine residue. The second moiety is the pentapeptide GKVLA, which is known to be a good substrate for transglutaminases. A four-glycine spacer and a Lys residue were inserted between the Lys and the Gln moieties for conjugation of the Gd-DOTAMA or the IRIS Blue-DOTAMA. This spacer-DOTAMA was chosen to keep the Gd- or IRIS Blue-complex far enough from interfering with the active site. The MRI and optical probes were therefore set as GKVLAK-(Gd-DOTAMA)-GGGGTVQQEL (Gd-DCCP16) and GKVLAK-(IRIS Blue-DOTAMA)-GGGGTVQQEL (DCCP16-IRIS Blue), respectively. In vivo effectiveness of the two agents was validated with MRI and optical mapping of transglutaminase-induced agent retention in mouse models of tumor xenografts and blood clotting (1). Noninvasive imaging of transglutaminase activity with Gd-DCCP16 or DCCP16-IRIS Blue provides an important tool for detecting and monitoring transglutaminase-targeted therapy in diverse pathologies including cancer, wound healing, myocardial infarction, and pregnancy failure associated with congenital FXIII deficiency (1). This chapter describes the results generated with DCCP16-IRIS Blue. The results obtained with Gd-DCCP16 were described in the chapter on Gd-DCCP16 in MICAD.

PMID:
21542553
[PubMed]
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