The anti-p185 her2/neu peptidomimetic (AHNP) is a small exo-cyclic peptide derived from the anti-p185 her2/neu rhumAb 4D5 (h4D5). AHNP mimics many but not all of the antitumor characteristics exhibited by h4D5. However, the pharmacokinetic profiles of AHNP are less than optimal for therapeutic or diagnostic purposes. To improve the binding affinity to p185 her2/neu and the antitumor efficacy, we have engineered a fusion protein containing AHNP and a nonimmunoglobulin protein scaffold, streptavidin (SA). The recombinant protein, AHNP-SA (ASA) bound to p185 her2/neu with high affinity, inhibited the proliferation of p185 her2/neu-overexpressing cells, and reduced tumor growth induced by p185 her2/neu-transformed cells. These data suggest that the bacterially produced tetrameric ASA can be used as an antibody-surrogate molecule. This class of molecule will play a role in the diagnosis and treatment of p185 her2/neu-related tumors. Our studies establish a general principle by which a small biologically active synthetic exo-cyclic peptide can be engineered to enhance functional aspects by structured oligomerization and can be produced recombinantly using bacterial expression.