title: Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif.
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-alpha (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 anti-tumor 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 Gly(3)-Arg(4). 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 beta-turn involving residues Gly(3)-Arg(4) and hydrogen bonding interactions between the backbone atoms of Asn(2) and Cys(5). These results suggest that the NGR motif has a strong propensity to form beta-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.
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Chimica del Riconoscimento Molecolare (CNR)-ICRM, 20131 Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.forename: Giacomo M S
authors.initials: GM
authors.lastname: De Mori
authors.forename: Anna
authors.initials: A
authors.lastname: Gasparri
authors.forename: Cristina
authors.initials: C
authors.lastname: Longoni
authors.forename: Angelina
authors.initials: A
authors.lastname: Sacchi
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001120:Arginine / Q000737:chemistry*; D001216:Asparagine / Q000737:chemistry*; D001667:Binding, Competitive; D015153:Blotting, Western; D003545:Cysteine / Q000737:chemistry; D004220:Disulfides; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013696:Temperature; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004220:Disulfides; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D001216:Asparagine; D001120:Arginine; D003545:Cysteine; D008558:Melphalan; D005998:Glycine