Nα-Methylation of arginine: Implications for cell-penetrating peptides

Abstract

The field of cell-penetrating peptides is dominated by the use of oligomers of arginine residues. Octanol–water partitioning in the presence of an anionic lipid is a validated proxy for cell-penetrative efficacy. Here, we add one, two, or three N-methyl groups to Ac-Arg-NH2 and examine the effects on octanol–water partitioning. In the absence of an anionic lipid, none of these arginine derivatives can be detected in the octanol layer. In the presence of sodium dodecanoate, however, increasing N-methylation correlates with increasing partitioning into octanol, which is predictive of higher cell-penetrative ability. We then evaluated fully Nα-methylated oligoarginine peptides and observed an increase in their cellular penetration compared with canonical oligoarginine peptides in some contexts. These findings indicate that a simple modification, Nα-methylation, can enhance the performance of cell-penetrating peptides.