𝔖 Bobbio Scriptorium
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Synthesis of bivalent inhibitors of eucaryotic proteasomes

✍ Scribed by Günther Loidl; Hans-Jürgen Musiol; Michael Groll; Robert Huber; Luis Moroder

Book ID
101284159
Publisher
John Wiley and Sons
Year
2000
Tongue
English
Weight
165 KB
Volume
6
Category
Article
ISSN
1075-2617

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✦ Synopsis

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.

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