Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif

Giorgio Colombo, Flavio Curnis, Giacomo M S De Mori, Anna Gasparri, Cristina Longoni, Angelina Sacchi, Renato Longhi, Angelo Corti

Research output: Contribution to journalArticle

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Abstract

Cyclic and linear peptides containing the Asn-Gly-Arg (NGR) motif have proven useful for delivering various anti-tumor compounds and viral particles to tumor vessels. We have investigated the role of cyclic constraints on the structure and tumor-homing properties of NGR peptides using tumor necrosis factor-α (TNF) derivatives containing disulfide-bridged (CNGRC-TNF) and linear (GNGRG-TNF) NGR domains. Experiments carried out in animal models showed that both GNGRG and CNGRC can target TNF to tumors. However, the antitumor activity of CNGRC-TNF was > 10-fold higher than that of GNGRG-TNF. Molecular dynamic simulation of cyclic CNGRC showed the presence of a bend geometry involving residues Gly3-Arg4. Molecular dynamic simulation of the same peptide without disulfide constraints showed that the most populated and thermodynamically favored configuration is characterized by the presence of a β-turn involving residues Gly3-Arg4 and hydrogen bonding interactions between the backbone atoms of Asn2 and Cys5. These results suggest that the NGR motif has a strong propensity to form β-turn in linear peptides and may explain the finding that GNGRG peptide can target TNF to tumors, albeit to a lower extent than CNGRC. The disulfide bridge constraint is critical for stabilizing the bent conformation and for increasing the tumor targeting efficiency.

Original languageEnglish
Pages (from-to)47891-47897
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number49
DOIs
Publication statusPublished - Dec 6 2002

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Cyclic Peptides
Structure-Activity Relationship
Tumors
Tumor Necrosis Factor-alpha
NGR peptide
Neoplasms
Disulfides
Peptides
Molecular Dynamics Simulation
Molecular dynamics
Computer simulation
Hydrogen Bonding
Virion
Conformations
Hydrogen bonds
Animals
Animal Models
Derivatives
Atoms
Geometry

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif. / Colombo, Giorgio; Curnis, Flavio; De Mori, Giacomo M S; Gasparri, Anna; Longoni, Cristina; Sacchi, Angelina; Longhi, Renato; Corti, Angelo.

In: Journal of Biological Chemistry, Vol. 277, No. 49, 06.12.2002, p. 47891-47897.

Research output: Contribution to journalArticle

Colombo, Giorgio ; Curnis, Flavio ; De Mori, Giacomo M S ; Gasparri, Anna ; Longoni, Cristina ; Sacchi, Angelina ; Longhi, Renato ; Corti, Angelo. / Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 49. pp. 47891-47897.
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