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