Synthesis of bivalent inhibitors of eucaryotic proteasomes

Based on the peculiar spatial array of the active sites in the internal cha mber of the multicatalytic proteasome, as derived from the X-ray structure of yeast proteasome, homo- and heterobivalent inhibitors were designed and synthesized to exploit the principle of multivalency for enhancing inhibiti on potency. Peptidic bis-aldehyde compounds of the octapeptide size were sy nthesized to address adjacent active sites, whilst a PEG spacer with a stat istical length distribution of 19-25 monomers was used to link mio identica l or different tripeptide aldehydes as binding heads. These bis-aldehyde co mpounds were synthesized applying both methods in solution and solid phase peptide synthesis. Bivalent binding was observed only for the PEG-spaced in hibitors suggesting that binding from the primed side prevents hemiacetal f ormation with the active site threonine residue. Copyright (C) 2000 Europea n Peptide Society and John Wiley & Sons, Ltd.