Synthesis and characterization of linear and cyclic ... - EleA@UniSA

importantly, excellent selectivity for protein targets that implicated in a range of human diseases. There
are many different interactions between peptoid and protein, and these interactions can induce a certain
inhibition, cellular uptake and delivery. Synthetic molecules capable of activating the expression of
specific genes would be valuable for the study of biological phenomena and could be therapeutically
useful. From a library of ~100000 peptoid hexamers, Kodadek and co-workers recently identified three
peptoids (24-26) with low micromolar binding affinities for the coactivator CREB-binding protein
(CBP) in vitro (Figure 1.5) 9 . This coactivator protein is involved in the transcription of a large number
of mammalian genes, and served as a target for the isolation of peptoid activation domain mimics. Of
the three peptoids, only 24 was selective for CBP, while peptoids 25 and 26 showed higher affinities for
bovine serum albumin. The authors concluded that the promiscuous binding of 25 and 26 could be
attributed to their relatively ―sticky‖ natures (i.e., aromatic, hydrophobic amide side chains).
Inhibitors of proteasome function that can intercept proteins targeted for degradation would be
valuable as both research tools and therapeutic agents. In 2007, Kodadek and co-workers 32 identified the
first chemical modulator of the proteasome 19S regulatory particle (which is part of the 26S proteasome,
an approximately 2.5 MDa multi-catalytic protease complex responsible for most non-lysosomal protein
degradation in eukaryotic cells). A ―one bead one compound‖ peptoid library was constructed by split
and pool synthesis.
Figure 1.5. Peptoid hexamers 24, 25, and 26 reported by Kodadek and co-workers and their
dissociation constants (KD) for coactivator CBP 33 . Peptoid 24 was able to function as a transcriptional
activation domain mimic (EC50 = 8 mM).
32 H. S. Lim, C. T. Archer, T. Kodadek J. Am. Chem. Soc., 2007, 129, 7750.
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