Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat. Mol Pharmacol 1999 Feb;55(2):332-8
Date
02/03/1999Pubmed ID
9927626DOI
10.1124/mol.55.2.332Scopus ID
2-s2.0-0033027727 (requires institutional sign-in at Scopus site) 138 CitationsAbstract
Mal II, a 19-residue peptide derived from the second type 1 properdin-like repeat of the antiangiogenic protein thrombospondin-1 (TSP-1), was inactive in angiogenesis assays. Yet the substitution of any one of three L-amino acids by their D-enantiomers conferred on this peptide a potent antiangiogenic activity approaching that of the intact 450-kDa TSP-1. Substituted peptides inhibited the migration of capillary endothelial cells with an ED50 of 8.5 nM for the D-Ile-15 substitution, 10 nM for the D-Ser-4 substitution, and 0.75 nM for the D-Ser-5 substitution. A peptide with D-Ile at position 15 could be shortened to its last seven amino acids with little loss in activity. Like whole TSP-1, the Mal II D-Ile derivative inhibited a broad range of angiogenic inducers, was selective for endothelial cells, and required CD36 receptor binding for activity. A variety of end modifications further improved peptide potency. An ethylamide-capped heptapeptide was also active systemically in that when injected i.p. it rendered mice unable to mount a corneal angiogenic response, suggesting the potential usefulness of such peptides as antiangiogenic therapeutics.
Author List
Dawson DW, Volpert OV, Pearce SF, Schneider AJ, Silverstein RL, Henkin J, Bouck NPAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AcetylationAmino Acid Sequence
Amino Acids
Animals
Cell Movement
Endothelial Growth Factors
Endothelium, Vascular
Fibroblast Growth Factor 1
Fibroblast Growth Factor 2
Interleukin-8
Isoleucine
Lymphokines
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Neovascularization, Pathologic
Oligopeptides
Platelet-Derived Growth Factor
Rats
Rats, Sprague-Dawley
Repetitive Sequences, Nucleic Acid
Sensitivity and Specificity
Serine
Stereoisomerism
Thrombospondin 1
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
