RT Journal Article SR Electronic T1 Three Distinct d-Amino Acid Substitutions Confer Potent Antiangiogenic Activity on an Inactive Peptide Derived from a Thrombospondin-1 Type 1 Repeat JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 332 OP 338 DO 10.1124/mol.55.2.332 VO 55 IS 2 A1 David W. Dawson A1 Olga V. Volpert A1 S. Frieda A. Pearce A1 Andrew J. Schneider A1 Roy L. Silverstein A1 Jack Henkin A1 Noël P. Bouck YR 1999 UL http://molpharm.aspetjournals.org/content/55/2/332.abstract AB 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 theird-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 withd-Ile at position 15 could be shortened to its last seven amino acids with little loss in activity. Like whole TSP-1, the Mal IId-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.