Rational design of a series of novel amphipathic cell-penetrating peptides.
A series of novel, amphipathic cell-penetrating peptides was developed based on a combination of the model amphipathic peptide sequence and modifications based on the strategies developed for PepFect and NickFect peptides. The aim was to study the role of amphipathicity for peptide uptake and to investigate if the modifications developed for PepFect peptides could be used to improve the uptake of another class of cell-penetrating peptides. The peptides were synthesized by solid phase peptide synthesis and characterized by circular dichroism spectroscopy. Non-covalent peptide-plasmid complexes were formed by co-incubation of the peptides and plasmids in water solution. The complexes were characterized by dynamic light scattering and cellular uptake of the complexes was studied in a luciferase-based plasmid transfection assay. A quantitative structure-activity relationship (QSAR) model of cellular uptake was developed using descriptors including hydrogen bonding, peptide charge and positions of nitrogen atoms. The peptides were found to be non-toxic and could efficiently transfect cells with plasmid DNA. Cellular uptake data was correlated to QSAR predictions and the predicted biological effects obtained from the model correlated well with experimental data. The QSAR model could improve the understanding of structural requirements for cell penetration, or could potentially be used to predict more efficient cell-penetrating peptides.
Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, Svante Arrhenius väg 21A, SE-10691 Stockholm, Sweden. Electronic address: jakob@neurochem.su.se.
Jakob
J
Regberg
Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, Svante Arrhenius väg 21A, SE-10691 Stockholm, Sweden; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, 10400 Bangkok, Thailand.
Artita
A
Srimanee
Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, Svante Arrhenius väg 21A, SE-10691 Stockholm, Sweden.
Mikael
M
Erlandsson
Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, Svante Arrhenius väg 21A, SE-10691 Stockholm, Sweden.
Rannar
R
Sillard
Tallinn University of Technology, Chemistry Department, Akadeemia Tee 15, Tallinn, Estonia.
Dimitar A
DA
Dobchev
Institute of Chemistry, University of Tartu, Ravila 14a, Tartu 50411, Estonia; Tallinn University of Technology, Chemistry Department, Akadeemia Tee 15, Tallinn, Estonia.
Mati
M
Karelson
Department of Neurochemistry, The Arrhenius Laboratories for Natural Sciences, Stockholm University, Svante Arrhenius väg 21A, SE-10691 Stockholm, Sweden; Laboratory of Molecular Biotechnology, Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.
Ulo
U
Langel
D000595:Amino Acid Sequence; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D021281:Quantitative Structure-Activity Relationship
D057846:Cell-Penetrating Peptides
Cell-penetrating peptide; Model amphipathic peptide; Plasmid transfection; QSAR; Structure–activity