1. Introduction 3452. Peptide nucleic acid (PNA) 3463. ‘Cell penetrating peptides’ (CPPs) 3464. Endosomal escape 3475. Cellular delivery of PNA 3476.In vivobioavailability of PNA 3497. References 350Recent results on the cellular delivery of antisense peptide nucleic acids (PNA) via peptide conjugation is briefly discussed, in particular in the context of endosomal entrapment and escape.
CPPs (cell-penetrating peptides) have given rise to much interest for the delivery of biomolecules such as peptides, proteins or ONs (oligonucleotides). CPPs and their conjugates were initially thought to translocate through the cell membrane by a non-endocytotic mechanism which has recently been re-evaluated. Basic-amino-acid-rich CPPs first interact with cell-surface proteoglycans before being internalized by endocytosis. Sequestration and degradation in endocytotic vesicles severely limits the cytoplasmic and nuclear delivery of the conjugated biomolecules. Accordingly, splicing correction by CPP-conjugated steric-block ON analogues is inefficient in the absence of endosomolytic agents. New arginine-rich CPPs allowing efficient splicing correction by conjugated PNAs (peptide nucleic acids) or PMO (phosphorodiamidate morpholino oligomer) steric blockers in the absence of endosomolytic agents have recently been defined in our group and are currently being characterized. They offer promising leads for the development of efficient cellular delivery vectors for therapeutic steric-block ON analogues.
<p>The discovery of high-affinity peptides to many
intracellular targets has become feasible
through the development of diverse macrocyclic peptide libraries. But lack of
cell permeability is a key feature
hampering the use of these peptides as therapeutics. Here, we develop a set of
small, cyclic peptide carriers that efficiently carry cargoes into the cytosol.
These peptides are cyclized via side-chain alkylation, which makes them ideal for the creation of
diverse mRNA or phage-displayed libraries with intrinsic cell permeability.</p>
Role of Cell-Penetrating Peptides in Intracellular Delivery of Peptide Nucleic Acids Targeting Hepadnaviral Replication