Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat

David W. Dawson, Olga V. Volpert, S. Frieda, Andrew J. Schneider, Roy L. Silverstein, Jack Henkin, Noël P. Bouck*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

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- IIe 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.

Original languageEnglish (US)
Pages (from-to)332-338
Number of pages7
JournalMolecular pharmacology
Volume55
Issue number2
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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