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Refinement of a Quantitative Structure–Activity Relationship Model for Prediction of Cell-Penetrating Peptide Based Transfection Systems
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-6189-3020
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-4604-6413
Stockholm University, Faculty of Science, Department of Neurochemistry.ORCID iD: 0000-0002-6440-7577
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2017 (English)In: International Journal of Peptide Research and Therapeutics, E-ISSN 1573-3904, Vol. 23, no 1, 91-100 p.Article in journal (Refereed) Published
Abstract [en]

Cell-penetrating peptide (CPP) based transfection systems (PBTS) are a promising class of drug delivery vectors. CPPs are short mainly cationic peptides capable of delivering cell non-permeant cargo to the interior of the cell. Some CPPs have the ability to form non-covalent complexes with oligonucleotides for gene therapy applications. In this study, we use quantitative structure–activity relationships (QSAR), a statistical method based on regression data analysis. Here, a fragment QSAR (FQSAR) model is developed to predict new peptides based on standard alpha helical conformers and Assisted Model Building with Energy Refinement molecular mechanics simulations of previous peptides. These new peptides were examined for plasmid transfection efficiency and compared with their predicted biological activity. The best predicted peptides were capable of achieving plasmid transfection with significant improvement compared to the previous generation of peptides. Our results demonstrate that FQSAR model refinement is an efficient method for optimizing PBTS for improved biological activity.

Place, publisher, year, edition, pages
2017. Vol. 23, no 1, 91-100 p.
Keyword [en]
CPP, PBTS, QSAR, AMBER, Peptide based transfection systems, Cell penetrating peptides, fragmentatio
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-140132DOI: 10.1007/s10989-016-9542-8ISI: 000393954000009OAI: oai:DiVA.org:su-140132DiVA: diva2:1077679
Funder
Swedish Research Council, 115363EU, FP7, Seventh Framework Programme
Available from: 2017-02-28 Created: 2017-02-28 Last updated: 2017-04-03Bibliographically approved
In thesis
1. In-silico design of peptide-based transfection systems, in-vitro validation, and up-take pathways investigation.
Open this publication in new window or tab >>In-silico design of peptide-based transfection systems, in-vitro validation, and up-take pathways investigation.
2017 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Cell-penetrating peptide-based transfection systems (PBTS) are a promising group of drug delivery vectors. Cell-penetrating peptides (CPPs) are short cationic peptides that are able of transporting cell non-permeant cargos into different cell types. Some CPPs can be used to form non-covalent complexes with oligonucleotides for gene delivery applications. For the potential use of CPPs as drug delivery tools, it is important to understand the mechanism of uptake. Here, a fragment quantitative structure–activity relationships (FQSAR) model is generated to predict novel peptides based on approved alpha helical conformers and assisted model construction with energy refinement molecular mechanics simulations of former peptides. The modeled peptides were examined for plasmid transfection efficiency and compared with their predicted biological activity. The best predicted peptides were efficient for plasmid transfection with significant enhancement compared to the former group of peptides. Our results confirm that FQSAR model refinement is an efficient method for optimizing PBTS for improved biological activity. Additionally, using RNA sequencing, we demonstrated the involvement of autophagy pathways in PBTS uptake.

Place, publisher, year, edition, pages
Department of Neurochemistry, Stockholm University, 2017. 50 p.
Keyword
Cell-penetrating peptides, QSAR, PepFect
National Category
Chemical Sciences Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
Identifiers
urn:nbn:se:su:diva-140139 (URN)
Presentation
2017-03-15, Heilbronnsalen, C458, Svante Arrhenius väg 16B, Stockholm, 14:00 (English)
Opponent
Supervisors
Available from: 2017-02-28 Created: 2017-02-28

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Dowaidar, MoatazRegberg, JakobLehto, TönisHällbrink, MattiasLangel, Ülo
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