The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid and study of its yttrium(III) complex

Moi, Min K.; Meares, Claude F.; DeNardo, Sally J.

doi:10.1021/ja00226a063

Cited by 177 publications

(94 citation statements)

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“…This sequence was found to be oxidized and tagged at the aspartic or glutamic acid, the arginine, and the lysine. Examination of the crystal structure of HSA 19 reveals that these residues occur in the center of the protein in the bottom cleft as shown in Figure 6B. This position is not known to be a metal-binding site on albumin but albumin does have multiple metal-binding sites.…”

Section: Identification Of the Tagged Peptidesmentioning

confidence: 99%

“…The methodology was validated by mapping the oxidation sites on an HSA crystal structure, 1AO6 19 . The crystals for this structure were grown from pooled HSA and from HSA expressed in Pichia pastoris.…”

Section: Identification Of the Tagged Peptidesmentioning

confidence: 99%

“…The oxidized amino acids are mapped onto an HSA crystal structure 1AO6 19 (www.rcsb.org) in Figures 5A and 5B. The oxidized amino acids are shown in red for definitively oxidized amino acids and in orange for those peptides with more than one candidate amino acid.…”

Section: Identification Of the Tagged Peptidesmentioning

confidence: 99%

“…Comparison of the observed masses to an in silico digest identifies the specific site of oxidation. In this paper, the oxidation sites of recombinant human serum albumin (rHSA), both in its native form and after FeEDTA-induced oxidation, are mapped onto an HSA crystal structure (pdb file: 1AO6, www.rcsb.org) 19 as proof of concept. A variety of modified residues were identified and all map onto the surface of the protein.…”

Section: Introductionmentioning

confidence: 99%

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Method to Site-Specifically Identify and Quantitate Carbonyl End Products of Protein Oxidation Using Oxidation-Dependent Element Coded Affinity Tags (O-ECAT) and NanoLiquid Chromatography Fourier Transform Mass Spectrometry

et al. 2006

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Protein oxidation is linked to cellular stress, aging, and disease. Protein oxidations that result in reactive species are of particular interest, since these reactive oxidation products may react with other proteins or biomolecules in an unmediated and irreversible fashion, providing a potential marker for a variety of disease mechanisms. We have developed a novel system to identify and quantitate, relative to other states, the sites of oxidation on a given protein. A specially designed Oxidation-dependent carbonyl-specific Element-Coded Affinity Mass Tag (O-ECAT), AOD, ((S)-2-(4-(2-aminooxy)-acetamido)-benzyl)-1, 4, 7, 10-tetraazacyclododecane-N, N′, N′′, N′′′-tetraacetic acid, is used to covalently tag the residues of a protein oxidized to aldehyde or keto end products.After proteolysis, the resulting AOD-tagged peptides are affinity purified, and analyzed by nanoLC-FTICR-MS, which provides high specificity in extracting co-eluting AOD mass pairs with a unique mass difference and affords relative quantitation based on isotopic ratios. Using this methodology, we have mapped the surface oxidation sites on a model protein, recombinant human serum albumin (rHSA) in its native form (as purchased) and after FeEDTA oxidation. A variety of modified amino acid residues including lysine, arginine, proline, histidine, threonine, aspartic and glutamic acids, were 3 found to be oxidized to aldehyde and keto end products. The sensitivity of this methodology is shown by the number of peptides identified, twenty peptides on the native protein and twenty-nine after surface oxidation using FeEDTA and ascorbate. All identified peptides map to the surface of the HSA crystal structure validating this method for identifying oxidized amino acids on protein surfaces. In relative quantitation experiments between FeEDTA oxidation and native protein oxidation, identified sites showed different relative propensities towards oxidation independent of amino acid residue. We expect to extend this methodology to study disease-related oxidation systems.

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Section: Identification Of the Tagged Peptidesmentioning

confidence: 99%

Section: Identification Of the Tagged Peptidesmentioning

confidence: 99%

Section: Identification Of the Tagged Peptidesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Method to Site-Specifically Identify and Quantitate Carbonyl End Products of Protein Oxidation Using Oxidation-Dependent Element Coded Affinity Tags (O-ECAT) and NanoLiquid Chromatography Fourier Transform Mass Spectrometry

et al. 2006

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“…5 The most commonly used chelators include polyaminocarboxylic acids (e.g., EDTA and DTPA) and their chemically modified derivatives such as DOTA. 5 The latter forms stable complexes with yttrium-90 ( 90 Y) 59 and is widely used as an effector in PRIT. However, alternative b-or a-emitting radionuclides can be used, as DOTA forms highly stable complexes with other isotopes such as 64 Cu, 67 Ga, 149 Pm, 166 62,63 In the second approach, biotin-conjugated antibody is used to target the tumor.…”

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confidence: 99%

Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

Walter

Press

Pagel

2010

Cancer Biotherapy and Radiopharmaceuticals

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SummationRadioimmunotherapy (RIT) has emerged as one of the most promising treatment options, particularly for hematologic malignancies. However, this approach has generally been limited by a suboptimal therapeutic index (target-to-nontarget ratio) and an inability to deliver sufficient radiation doses to tumors selectively. Pretargeted RIT (PRIT) circumvents these limitations by separating the targeting vehicle from the subsequently administered therapeutic radioisotope, which binds to the tumor-localized antibody or is quickly excreted if unbound. A growing number of preclinical proof-of-principle studies demonstrate that PRIT is feasible and safe and provides improved directed radionuclide delivery to malignant cells compared with conventional RIT while sparing normal cells from nonspecific radiotoxicity. Early phase clinical studies corroborate these preclinical findings and suggest better efficacy and lesser toxicities in patients with hematologic and other malignancies. With continued research, PRIT-based treatment strategies promise to become cornerstones to improved outcomes for cancer patients despite their complexities.

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Comparative toxicity studies of yttrium-90 mx-dtpa and 2-it-bad conjugated monoclonal antibody (bre-3)

DeNardo

Kroger

DeNardo

et al. 1994

Cancer

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Background. BrE‐3 is a monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium‐90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene‐triaminepentaacetic acid (MX‐DTPA) or bromoacetamidobenzyl‐1,4,7,10‐tetraazocyclododecane‐N,N′,N″,N″‐tetraacetic acid (BAD). Methods and Results. Bone marrow hematopoietic toxicity was dose‐limiting and the source of death for both chelators. The LD50 for 90Y‐BrE‐3‐MX‐DTPA was 220.9 μCi, and that for 90Y‐BrE‐3‐2IT‐BAD was 307.8 μCi. Whole‐body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX‐DTPA was used as the chelator. Conclusions. These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species. Cancer 1994 73:1012–22.

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The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid and study of its yttrium(III) complex

Cited by 177 publications

References 1 publication

Method to Site-Specifically Identify and Quantitate Carbonyl End Products of Protein Oxidation Using Oxidation-Dependent Element Coded Affinity Tags (O-ECAT) and NanoLiquid Chromatography Fourier Transform Mass Spectrometry

Method to Site-Specifically Identify and Quantitate Carbonyl End Products of Protein Oxidation Using Oxidation-Dependent Element Coded Affinity Tags (O-ECAT) and NanoLiquid Chromatography Fourier Transform Mass Spectrometry

Pretargeted Radioimmunotherapy for Hematologic and Other Malignancies

Comparative toxicity studies of yttrium-90 mx-dtpa and 2-it-bad conjugated monoclonal antibody (bre-3)

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