A small series of peptide mimics was designed and synthesized to contain a
heterocyclic ring in place of the potentially labile N-terminal peptide bond of
the tetrapeptide containing the Smac-XIAP-binding motif. Two Smac mimics were
shown to bind to the BIR3 domain of XIAP with moderate affinity and one
displayed increased activity in cells relative to the Smac peptides. The
structures of BIR3-XIAP in complex with a Smac peptide and a peptide mimic were
solved and analyzed to elucidate the structure-activity relationship surrounding
the Smac-binding domain within BIR3-XIAP.
