Synthesis and activity of partial retro-inverso analogs of the antimetastatic laminin-derived peptide, YIGSR-NH2.
This paper describes the synthesis and biological evaluation of six partial retro-inverso peptidomimetic analogs of YIGSR-NH2, a synthetic peptide from the beta 1 chain of laminin, which has antimetastatic activity. The intent was to improve the antimetastatic potency of YIGSR-NH2 by limiting the in vivo enzymatic degradation through the incorporation of fraudulent peptide bonds. We have prepared the following retro-inverso peptides, Tyr-Ile-Gly-Ser-gArg-CHO (1), Tyr-gIle-mGly-Ser-Arg-NH2 (2), Tyr-gIle-mGly-Ser-gArg-CHO (3), gTyr-D-rIle-mGly-Ser-Arg-NH2 (4), Tyr-Ile-Gly-gSer-D-rArg-CHO (5) and Tyr-gIle-rGly-D-rSer-D-rArg-CHO (6). In vitro assays for B16F10 melanoma cell adhesion showed no significant activity for these six peptides. Peptides 1-3, 5 and 6 were further tested, in vivo, for their ability to inhibit tumor metastases to the lung in mice injected in the tail vein with B16F10 melanoma cells. All five of the retro-inverso peptides tested showed statistically significant inhibition of metastasis, but the most active peptides were 5 and 6, which showed 57 and 69% inhibition of metastasis, respectively.
Zhao
M
M
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania, USA.
Kleinman
H K
HK
Mokotoff
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015195:Drug Design; D005260:Female; D007797:Laminin / Q000031:analogs & derivatives* / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary*; D013058:Mass Spectrometry; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011487:Protein Conformation; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007797:Laminin; D009842:Oligopeptides; C081572:tyrosyl-isoleucyl-glycyl-seryl-argininamide