title: Synthesis of bivalent inhibitors of eucaryotic proteasomes.
abstract: Based on the peculiar spatial array of the active sites in the internal chamber 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 inhibition potency. Peptidic bis-aldehyde compounds of the octapeptide size were synthesized to address adjacent active sites, whilst a PEG spacer with a statistical length distribution of 19-25 monomers was used to link two identical or different tripeptide aldehydes as binding heads. These bis-aldehyde compounds were synthesized applying both methods in solution and solid phase peptide synthesis. Bivalent binding was observed only for the PEG-spaced inhibitors suggesting that binding from the primed side prevents hemiacetal formation with the active site threonine residue.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Loidl
authors.forename: H J
authors.initials: HJ
authors.lastname: Musiol
authors.forename: M
authors.initials: M
authors.lastname: Groll
authors.forename: R
authors.initials: R
authors.lastname: Huber
authors.forename: L
authors.initials: L
authors.lastname: Moroder
mesh_terms: D053818:Chymases; D002918:Chymotrypsin / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005057:Eukaryotic Cells / Q000648:ultrastructure; D005656:Fungal Proteins / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D009097:Multienzyme Complexes / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000138:chemical synthesis*; D011092:Polyethylene Glycols / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D012697:Serine Endopeptidases / Q000378:metabolism; D014357:Trypsin / Q000494:pharmacology; D053802:Tryptases
chemical_list: D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D009097:Multienzyme Complexes; D010455:Peptides; D011092:Polyethylene Glycols; D012697:Serine Endopeptidases; C083294:chymase 2; D002918:Chymotrypsin; D053818:Chymases; D014357:Trypsin; D053802:Tryptases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex