ArticleThe Journal of biological chemistry2010
Critical role of flanking residues in NGR-to-isoDGR transition and CD13/integrin receptor switching.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 85 citations in OpenAlex.
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- Repair of Isoaspartyl Residues by PCMT1 and Kidney Fibrosis.Journal of the American Society of Nephrology : JASN · 2025Article
- Radiolabeled NGR-Based Heterodimers for Angiogenesis Imaging: A Review of Preclinical Studies.Cancers · 2023Review
- Structural insights into regulation of CCN protein activities and functions.Journal of cell communication and signaling · 2023Review
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- Ceruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function.International journal of molecular sciences · 2021Review
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- Cyclic RGD andMolecules (Basel, Switzerland) · 2020Article
- αv-Class integrin binding to fibronectin is solely mediated by RGD and unaffected by an RGE mutation.The Journal of cell biology · 2020Article
- In Vivo Tumor Growth Inhibition and Antiangiogenic Effect of Cyclic NGR Peptide-Daunorubicin Conjugates Developed for Targeted Drug Delivery.Pathology oncology research : POR · 2020Article
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- Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling.International journal of molecular sciences · 2019Article
- The aspartimide problem persists: Fluorenylmethyloxycarbonyl-solid-phase peptide synthesis (Fmoc-SPPS) chain termination due to formation of N-terminal piperazine-2,5-diones.Journal of peptide science : an official publication of the European Peptide Society · 2019Article
- Phosphate-Catalyzed Succinimide Formation from an NGR-Containing Cyclic Peptide: A Novel Mechanism for Deammoniation of the Tetrahedral Intermediate.Molecules (Basel, Switzerland) · 2018Article
- Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting.Beilstein journal of organic chemistry · 2018Article
- Development of novel cyclic NGR peptide-daunomycin conjugates with dual targeting property.Beilstein journal of organic chemistry · 2018Article
- Molecular Imaging of Aminopeptidase N in Cancer and Angiogenesis.Contrast media & molecular imaging · 2018Review
- GlycineAdvanced functional materials · 2017Article
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Authors and funding
12 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Various NGR-containing peptides have been exploited for targeted delivery of drugs to CD13-positive tumor neovasculature. Recent studies have shown that compounds containing this motif can rapidly deamidate and generate isoaspartate-glycine-arginine (isoDGR), a ligand of alphavbeta3-integrin that can be also exploited for drug delivery to tumors. We have investigated the role of NGR and isoDGR peptide scaffolds on their biochemical and biological properties. Peptides containing the cyclic CNGRC sequence could bind CD13-positive endothelial cells more efficiently than those containing linear GNGRG. Peptide degradation studies showed that cyclic peptides mostly undergo NGR-to-isoDGR transition and CD13/integrin switching, whereas linear peptides mainly undergo degradation reactions involving the alpha-amino group, which generate non-functional six/seven-membered ring compounds, unable to bind alphavbeta3, and small amount of isoDGR. Structure-activity studies showed that cyclic isoDGR could bind alphavbeta3 with an affinity >100-fold higher than that of linear isoDGR and inhibited endothelial cell adhesion and tumor growth more efficiently. Cyclic isoDGR could also bind other integrins (alphavbeta5, alphavbeta6, alphavbeta8, and alpha5beta1), although with 10-100-fold lower affinity. Peptide linearization caused loss of affinity for all integrins and loss of specificity, whereas alpha-amino group acetylation increased the affinity for all tested integrins, but caused loss of specificity. These results highlight the critical role of molecular scaffold on the biological properties of NGR/isoDGR peptides. These findings may have important implications for the design and development of anticancer drugs or tumor neovasculature-imaging compounds, and for the potential function of different NGR/isoDGR sites in natural proteins.
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