A growing body of evidence suggests that
peptides containing the
Asn-Gly-Arg (NGR) motif can selectively recognize
tumor neovasculature and can be used, therefore, for
ligand-directed targeted delivery of various drugs and particles to
tumors or to other tissues with an angiogenesis component. The neovasculature binding properties of these
peptides rely on the interaction with an endothelium-associated form of
aminopeptidase N (CD13), an
enzyme that has been implicated in angiogenesis and
tumor growth. Recent studies have shown that NGR can rapidly convert to
isoaspartate-
glycine-
arginine (isoDGR) by
asparagine deamidation, generating alpha(v)beta(3)
ligands capable of affecting endothelial cell functions and
tumor growth. This review focuses on structural and functional properties of the NGR motif and its application in
drug development for angiogenesis-dependent diseases. Furthermore, we discuss the time-dependent transition of NGR to isoDGR in natural
proteins, such as
fibronectins, and its potential role of as a "molecular timer" for generating new binding sites for
integrins impli-cated in angiogenesis.