Effect of small molecule signaling in PepFect14 transfection.
Benzamides
/ metabolism
Cell-Penetrating Peptides
/ metabolism
Drug Delivery Systems
Endocytosis
HeLa Cells
High-Throughput Screening Assays
Humans
Imidazoles
/ metabolism
Lipopeptides
/ metabolism
Nanoparticles
/ metabolism
Oligonucleotides
/ genetics
Peptides
/ metabolism
Pyridines
/ metabolism
Receptors, Cell Surface
/ metabolism
Signal Transduction
Transfection
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
07
2019
accepted:
10
01
2020
entrez:
31
1
2020
pubmed:
31
1
2020
medline:
19
5
2020
Statut:
epublish
Résumé
Cell-penetrating peptides can be used to deliver oligonucleotide-based cargoes into cells. Previous studies have shown that the use of small molecule drugs could be an efficient method to increase the efficacy of delivery of oligonucleotides by cell-penetrating peptides either as targeting agents that can be used in formulation with the cell-penetrating peptide and its cargo or as cell signaling modulators that facilitates the cellular uptake of the treatment. This study presents two aims. The first aim is the identification of small molecule drugs that would induce a synergic effect on the transfection of splice correcting oligonucleotides assisted by PepFect14. The second aim is to identify the mechanisms behind the effect of small molecule drugs modulation of cell-penetrating peptide assisted transfection of oligonucleotides. Through an optimized, high-throughput luciferase assay for short oligonucleotide delivery using cell-penetrating peptides, and the simultaneous addition of a small molecule drug library, we show that three small molecule drugs (MPEP, VU0357121 and Ciproxifan) induced an increase in the transfection efficacy of PepFect14 in complex with a short single-stranded oligonucleotide in HeLa pLuc705 cells. These three drugs are described in the literature to be highly specific for their respective target receptors. However, none of those receptors are expressed in our cell line, indicating a yet non-described pathway of action for these small molecules. We show that the indicated small molecules, without interfering with the particles formed by PepFect14 and the oligonucleotide, interfere via still unidentified interactions in cell signaling, leading to an up-regulation of endocytosis and a higher efficacy in the delivery of short splice correcting oligonucleotides in complex with PepFect14.
Identifiants
pubmed: 31999754
doi: 10.1371/journal.pone.0228189
pii: PONE-D-19-19893
pmc: PMC6992163
doi:
Substances chimiques
Benzamides
0
Cell-Penetrating Peptides
0
Imidazoles
0
Lipopeptides
0
Oligonucleotides
0
PepFect14 peptide
0
Peptides
0
Pyridines
0
Receptors, Cell Surface
0
VU0357121
0
ciproxifan
5EVQ7IRG99
6-methyl-2-(phenylethynyl)pyridine
7VC0YVI27Y
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0228189Déclaration de conflit d'intérêts
The authors received funding in part from the European Federation of Pharmaceutical Industries and Associations, EFPIA. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development, or marketed products to declare.
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