Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat.
Mol Pharmacol
; 55(2): 332-8, 1999 Feb.
Article
in En
| MEDLINE
| ID: mdl-9927626
ABSTRACT
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oligopeptides
/
Thrombospondin 1
/
Amino Acids
/
Neovascularization, Pathologic
Type of study:
Diagnostic_studies
Limits:
Animals
Language:
En
Journal:
Mol Pharmacol
Year:
1999
Document type:
Article
Affiliation country:
Estados Unidos