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Vol. 55, Issue 2, 332-338, February 1999

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 A. Pearce, Andrew J. Schneider, Roy L. Silverstein, Jack Henkin, and Noël P. Bouck

Department of Microbiology-Immunology and Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois (D.W.D, O.V.V., N.P.B.); Department of Medicine, Division of Hematology-Oncology, Cornell University Medical College, New York, New York (S.F.A.P., R.L.S.); and Abbott Laboratories, Abbott Park, Illinois (A.J.S., J.H.)

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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics