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. 2000 Jan;6(1):36-46.
doi: 10.1002/(SICI)1099-1387(200001)6:1<36::AID-PSC232>3.0.CO;2-2.

Synthesis of bivalent inhibitors of eucaryotic proteasomes

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Synthesis of bivalent inhibitors of eucaryotic proteasomes

G Loidl et al. J Pept Sci. 2000 Jan.

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.

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