Structural and antitumor properties of the YSNSG cyclopeptide derived from tumstatin.
We previously demonstrated that the NC1[alpha3(IV)185-191] CNYYSNS peptide inhibited in vivo tumor progression. The YSNS motif formed a beta turn crucial for biological activity. The aim of the present study was to design a YSNSG cyclopeptide with a constrained beta turn on the YSNS residues more stable than CNYYSNS. By nuclear magnetic resonance and molecular modeling, we demonstrated that the YSNSG cyclopeptide actually adopted the expected beta-turn conformation. It promoted melanoma cell adhesion and prevented their adhesion to the native peptide. It inhibited in vitro cell proliferation and migration through Matrigel by downregulating proteolytic cascades. Moreover, intraperitoneal administration of the YSNSG cyclopeptide inhibited melanoma progression far more efficiently than the native peptide. The increased solubility and stability at low pH of the YSNSG cyclopeptide suggest this peptide as a potent antitumor therapeutic agent.
Thevenard
Jessica
J
Laboratoire de Biochimie Médicale et Biologie Moléculaire, CNRS UMR 6198, IFR 53 Biomolécules, Université de Reims Champagne-Ardenne, 51095 Reims, France.
Floquet
Nicolas
N
Ramont
Laurent
L
Prost
Elise
E
Nuzillard
Jean-Marc
JM
Dauchez
Manuel
M
Yezid
Hocine
H
Alix
Alain J P
AJ
Maquart
François-Xavier
FX
Monboisse
Jean-Claude
JC
Brassart-Pasco
Sylvie
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D024141:Collagen Type IV / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation
D000970:Antineoplastic Agents; D001324:Autoantigens; D024141:Collagen Type IV; D010456:Peptides, Cyclic; C521292:YSNSG cyclopeptide; C057112:type IV collagen alpha3 chain