A Quantitative Comparison of Cytosolic Uptake of α-ABpeptoids and Peptides

Abstract

Peptidomimetics have been developed to overcome the shortcomings of peptides in drug discovery area. In particular, peptoids, oligomers of N-substituted glycines, provide enhanced cell permeability compared to peptides. However, peptoids lack conformational rigidity, which could lead to weak binding affinity toward biopolymers. Several strategies have been investigated to reduce the flexible nature of peptoids. Especially, α-Alkyl beta-peptoids (α-ABpeptoids) were reported to have characteristic CD spectra, implying to have ordered conformation. Besides this study, it was demonstrated that conformationally rigid molecules show improved cellular uptake. Although cell permeability is an important property for drug development, no systematic investigation of α-ABpeptoids was made. To validate the therapeutic potential of α-ABpeptoids, we made a quantitative evaluation of cell permeability of α-ABpeptoids and peptides. For uncharged oligomers, α-ABpeptoids showed enhanced cell permeability compared to peptide counterparts, regardless of their size and side chains. Of note, uncharged α-ABpeptoids displayed cytosolic abundance even better than the well-known cell penetrating peptide, polyR8, showing significance in cell permeability. Also, we studied cellular uptake mechanism α-ABpeptoid oligomers to determine the effect of net charge and size.