Peptoid-peptide hybrids are oligomeric peptidomimetics that contain one or more N-substituted glycine residues. In these hybrids, the side chains of one or several amino acids are "shifted" from the alpha-carbon atom to the amide nitrogen atom. A library of phosphorylated peptoid-peptide hybrids derived from the sequence pTyr-Glu-Thr-Leu was synthesized and tested for binding to the tandem SH2 domain of the protein tyrosine kinase Syk. A considerable influence of the side chain position was observed. Compounds 19-21, 24, and 25 comprising a peptoid NpTyr and/or NGlu residue did not show any binding. Compounds 22, 23, and 26 containing an NhThr (hThr=homothreonine) and/or NLeu peptoid residue showed binding with IC(50) values that were only five to eight times higher than that of the tetrapeptide lead compound 18. These data show that side chain shifting is possible with retention of binding capacity, but only at the two C-terminal residues of the tetramer. This method of a peptoid scan using peptoid-peptide hybrids appears to be very useful to explore to what extent a peptide sequence can be transformed into a peptoid while retaining its affinity.