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.
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