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 language | English |
|---|---|
| Pages (from-to) | 47891-47897 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 277 |
| Issue number | 49 |
| DOIs | |
| Publication status | Published - Dec 6 2002 |
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ASJC Scopus subject areas
- Biochemistry
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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 journal › Article
}
TY - JOUR
T1 - Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif
AU - Colombo, Giorgio
AU - Curnis, Flavio
AU - De Mori, Giacomo M S
AU - Gasparri, Anna
AU - Longoni, Cristina
AU - Sacchi, Angelina
AU - Longhi, Renato
AU - Corti, Angelo
PY - 2002/12/6
Y1 - 2002/12/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0346668331&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0346668331&partnerID=8YFLogxK
U2 - 10.1074/jbc.M207500200
DO - 10.1074/jbc.M207500200
M3 - Article
C2 - 12372830
AN - SCOPUS:0346668331
VL - 277
SP - 47891
EP - 47897
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 49
ER -