Evaluation of the cell permeability of bicyclic peptoids and bicyclic peptide-peptoid hybrids.

Bicyclization has proven to be an effective strategy for significantly restricting conformational flexibility in peptides and peptidomimetics such as peptoids. Such constrained bicyclic peptoids would have far higher conformational rigidity than monocyclic and linear ones, allowing them to have enhanced binding affinity and selectivity for their biological targets. Herein, we show that bicyclic peptoids have superior cellular uptake efficiency than their linear counterparts regardless of their side chains and ring sizes. As a representative example, an 8-mer bicyclic peptoid achieves a CP ₅₀ value of 1.2 μM, which is > 5-times superior to the corresponding linear peptoid. Additionally, we also demonstrate that bicyclic peptide-peptoid hybrids are much more cell-permeable than native peptides. Due to their favorable properties including improved cellular uptake, resistance to proteolytic degradation, relatively large sizes, and enormous structural diversity, constrained bicyclic peptoids and peptide-peptoid hybrids will play an important role as potential drug leads, especially in targeting intracellular protein-protein interactions, which are traditionally considered undruggable.
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