Synthesis of Short Peptides with Perfluoroalkyl Side Chains and Evaluation of Their Cellular Uptake Efficiency

Abstract

AbstractWith an increasing demand for macromolecular biotherapeutics, the issue of their poor cell‐penetrating abilities requires viable and relevant solutions. Herein, we report tripeptides bearing an amino acid with a perfluoroalkyl (RF) group adjacent to the α‐carbon. RF‐containing tripeptides were synthesized and evaluated for their ability to transport a conjugated hydrophilic dye (Alexa Fluor 647) into the cells. RF‐containing tripeptides with the fluorophore showed high cellular uptake efficiency and none of them were cytotoxic. Interestingly, we demonstrated that the absolute configuration of perfluoroalkylated amino acids (RF‐AAs) affects not only nanoparticle formation but also the cell permeability of the tripeptides. These novel RF‐containing tripeptides are potentially useful as short and noncationic cell‐penetrating peptides (CPPs).