Comparison of Cell Permeability of Cyclic Peptoids and Linear Peptoids.

Cyclic peptoids are emerging as an attractive class of peptidomimetics. Compared to their linear counterparts, cyclic peptoids should have increased conformational rigidity and preorganized structures, enabling them to bind more tightly to target proteins without major entropy penalty. Because cyclic peptoids lack the amide protons in their backbones like linear peptoids, it is perceived that cyclic peptoids are seemingly cell permeable as much as linear peptoids. However, no systematic investigation for cell permeability of cyclic peptoids has been reported yet. Here, we, for the first time, demonstrate that cyclic peptoids are far more cell permeable than linear counterparts irrespective of their size and side chains. This study highlights that cyclic peptoids, along with combinatorial library and high-throughput screening technologies, will serve as a rich source of protein binding molecules, particularly targeting intracellular proteins, given their excellent cell permeability in addition to their conformational rigidity and proteolytic stability.

Oligomers of N-Substituted ß(2)-Homoalanines: Peptoids with Backbone Chirality.

A new class of peptoid-based peptidomimetics composed of oligomers of N-substituted ß(2)-homoalanines is reported. Design, solid-phase synthesis, and preliminary circular dichroism studies of oligomers of N-alkylated ß(2)-homoalanines consisting of up to 8-mers are described.

A Chemical Inhibitor of the Skp2/p300 Interaction that Promotes p53-Mediated Apoptosis.

Skp2 is thought to have two critical roles in tumorigenesis. As part of the SCF(Skp2) ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 also blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Herein, we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screen of a combinatorial cyclic peptoid library identified an inhibitor that binds to Skp2 and interferes with the Skp2/p300 interaction. We show that antagonism of the Skp2/p300 interaction by the inhibitor leads to p300-mediated p53 acetylation, resulting in p53-mediated apoptosis in cancer cells, without affecting Skp2 proteolytic activity. Our results suggest that inhibition of the Skp2/p300 interaction has a great potential as a new anticancer strategy, and our Skp2 inhibitor can be developed as a chemical probe to delineate Skp2 non-proteolytic function in tumorigenesis.