bc5b00023_si_001.pdf (11.45 MB)
Macrocyclic Cell Penetrating Peptides: A Study of Structure-Penetration Properties
journal contribution
posted on 2015-03-18, 00:00 authored by Hassan Traboulsi, Heidi Larkin, Marc-André Bonin, Leonid Volkov, Christine
L. Lavoie, Éric MarsaultArginine-rich cell penetrating peptides
are short cationic peptides
able to cross biological membranes despite their peptidic character.
In order to optimize their penetration properties and further elucidate
their mechanisms of cellular entry, these peptides have been intensively
studied for the last two decades. Although several parameters are
simultaneously involved in the internalization mechanism, recent studies
suggest that structural modifications influence cellular internalization.
Particularly, backbone rigidification, including macrocyclization,
was found to enhance proteolytic stability and cellular uptake. In
the present work, we describe the synthesis of macrocyclic arginine-rich
cell penetrating peptides and study their cellular uptake properties
using a combination of flow cytometry and confocal microscopy. By
varying ring size, site of cyclization, and stereochemistry of the
arginine residues, we studied their structure–uptake relationship
and showed that the mode and site of cyclization as well as the stereochemistry
influence cellular uptake. This study led to the identification of
a hepta-arginine macrocycle as efficient as its linear nona-arginine
congener to enter cells.