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

Tamara Lützenburg,Nele Burdina,Matthias S Scholz,Ines Neundorf

doi:10.3390/pharmaceutics13122075

Tamara Lützenburg, Nele Burdina + Show 2 more

Open Access

https://doi.org/10.3390/pharmaceutics13122075

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Journal: Pharmaceutics	Publication Date: Dec 3, 2021
Citations: 3	License type: CC BY 4.0

Affiliation: University of Cologne, University of Bonn

Abstract

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.

Highlights

Active peptides often develop distinct and stable conformations when in proximity to their binding partners
Our findings presented in this work prove that introducing CBs to cell-penetrating peptides modulates and enhances their membrane activity
We could demonstrate that the increased hydrophobicity caused by the attached CBs combined with the higher alphahelical content significantly improved lipid phase interaction and cellular uptake into HeLa cells for the cell-penetrating peptides (CPPs) sC18

Summary

Introduction

Active peptides often develop distinct and stable conformations when in proximity to their binding partners. It has been found out that the presence of hydrophobic amino acids, or the attachment of other hydrophobic moieties, e.g., lipidation, might further induce superior interaction with lipid bilayers [15,17,18] In this respect, so-called car(ba)boranes (CBs) have emerged as interesting lipophilic substitutes and were already integrated as pharmacophores into different small molecule drugs. The incorporation of carboranes into therapeutic peptides was already described [19,20,21] In this regard, CB-peptide conjugates turned out to be promising for application in tumorselective boron neutron capture therapy (BNCT), and CPPs were used to create such boron delivery systems [22,23]. As a model CPP, we used sC18, which was developed in our group and turned out as a useful transporter for many different cargoes [25,26,27,28,29]

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