Improving Membrane Activity and Cargo Delivery Efficacy of a Cell-Penetrating Peptide by Loading with Carboranes

Pharmaceutics. 2021 Dec 3;13(12):2075. doi: 10.3390/pharmaceutics13122075.


Cell-penetrating peptides (CPPs) have emerged as versatile tools to increase the intracellular accumulation of different kinds of cargoes. For an efficient cellular uptake and drug delivery, their organization into a distinct and stable secondary structure at the outer surface of the plasma membrane is a hallmark and supports optimal lipid-peptide interactions. Incorporation of hydrophobic moieties, such as carboranes (CBs), has the potential to increase the lipophilicity of peptides, and thus, to facilitate the formation of secondary structures. Herein, we present synthesis and biophysical as well as biological characterization of carborane-CPP conjugates having incorporated one or more CB clusters. Our results highlight the possibility to modulate the secondary structure of CPPs by the addition of CB's leading to constructs with altered membrane activity and promising use in terms of nucleic acid delivery.

Keywords: alpha-helix stabilization; cell-penetrating peptides; lipid–peptide interaction; peptide engineering; secondary structure.