title: Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome.
abstract: This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inhibited in the low nanomolar range and proved to be selective for the proteasome over other serine and cysteine proteases, particularly when compared to linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently inhibited activation of nuclear factor-κB (NF-κB) transcription factor by blocking proteasomal degradation of the inhibitor protein IκBα after cytokine stimulation. Due to their covalent mechanism of binding these compounds represent a 1000-fold increase in inhibitory potency over previously reported noncovalently binding TMC-95 analogues. Molecular modeling of the macrocyclic peptides confirms the preference of the large S3 pocket for large, hydrophobic residues and the ability to exploit this to improve selectivity of proteasome inhibitors.
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Wilson
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health , Neuherberg 85764, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Meininger
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: Zack
authors.initials: Z
authors.lastname: Strater
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Steiner
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: Frederick
authors.initials: F
authors.lastname: Tomlin
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: Haya
authors.initials: H
authors.lastname: Jamali
authors.affiliation: Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München-German Research Center for Environmental Health , Neuherberg 85764, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.affiliation: Department of Chemistry, Whitman College , Walla Walla, Washington 99362, United States.
authors.forename: Marion G
authors.initials: MG
authors.lastname: Götz
keywords: Proteasome; aldehyde; inhibitor; macrocycle; multiple myeloma