PT  - JOURNAL ARTICLE
AU  - Dawson, David W.
AU  - Volpert, Olga V.
AU  - Pearce, S. Frieda A.
AU  - Schneider, Andrew J.
AU  - Silverstein, Roy L.
AU  - Henkin, Jack
AU  - Bouck, Noël P.
TI  - Three Distinct <span class="sc">d</span>-Amino Acid Substitutions Confer Potent Antiangiogenic Activity on an Inactive Peptide Derived from a Thrombospondin-1 Type 1 Repeat
AID  - 10.1124/mol.55.2.332
DP  - 1999 Feb 01
TA  - Molecular Pharmacology
PG  - 332--338
VI  - 55
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/55/2/332.short
4100  - http://molpharm.aspetjournals.org/content/55/2/332.full
SO  - Mol Pharmacol1999 Feb 01; 55
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.