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Synthesis of bivalent inhibitors of eucaryotic proteasomes
Author(s) -
Loidl Günther,
Musiol HansJürgen,
Groll Michael,
Huber Robert,
Moroder Luis
Publication year - 2000
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(200001)6:1<36::aid-psc232>3.0.co;2-2
Subject(s) - tripeptide , chemistry , proteasome , aldehyde , peptide , bivalent (engine) , stereochemistry , active site , residue (chemistry) , threonine , monomer , peg ratio , peptide synthesis , binding site , biochemistry , yeast , enzyme , organic chemistry , serine , catalysis , polymer , finance , metal , economics
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. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.