Stockholms universitet
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Ülo LangelProfessor Emeritus

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Forskningsprojekt

Utveckling av cellulära transportörer

Cellpenetrerande peptider, CPP, har en funktion som cellulära transportörer över biologiska membran. Då dessa CPP, eller transportaner, även kan bära med sig andra ämnen, såsom ett protein, så kan de bidra till nya metoder för forskning och terapeutiska applikationer. Mekanismerna bakom denna cellulära leverans är fortfarande oklar och är värd att studera i detalj. Utöver detta ligger vårt intresse i nuläget också i möjligheten att transportera läkemedel över blod-hjärn-barriären. Cellulär leverans av peptider, korta oligonukleotider såsom siRNA, peptide nukleinsyra oligomerer, proteiner och även transfektionsplasmider har möjliggjorts med CPP.
 

Utvalda publikationer

1. Langel,Ü. (2021) Cell-penetrating peptides and transportan. Pharmaceutics. Special Issue “Current state in the Field of Cell-Penetrating Peptides as honorific issue for Professor Ülo Langel”. 13(7) : 987, 1-31.

2. Porosk,L., Gaidutšik,I., and Langel,Ü. (2021) Approaches for the discovery of new cell-penetrating peptides. Expert Opinion On Drug Discovery, 16(5), 553-565, DOI: 10.1080/17460441.2021.1851187.

3. Porosk,L., Põhako,K., Arukuusk,P., and Langel,Ü. (2021) Cell-penetrating peptides predicted from CASC3, AKIP1 and AHRR proteins. Frontiers in Pharmacology, 12, article 716226, 1-10. doi: 10.3389/fphar.2021.716226

4. Zorko,M., Jones,S., and Langel,Ü. (2022) Cell-penetrating peptides in protein mimicry and cancer therapeutics. Advanced Drug Delivery Reviews, 180, 114044, 1-17.

5. Cerrato,C.P., and Langel,Ü. (2022) An update on cell-penetrating peptides with intracellular organelle targeting, Expert Opinion on Drug Delivery, DOI: 10.1080/17425247.2022.203478, 19(2), 133-146.

6. Porosk,L., Härk,H.H., Bicev,R.N., Gaidutšik,I., Nebogatova, J., Armolik,E-J., Arukuusk,P., de Silva,E.R. and Langel,Ü., (2023) Aggregation limiting cell-penetrating peptides derived from protein signal sequences. Int. J. Mol. Sci. 2023, 24(5), 4277, 1-20. doi.org/10.3390/ijms24054277.

7. Saldanha,L., Langel,Ü., and Vale,N. (2023) In-silico Studies to Support Vaccine Development, Pharmaceutics, 15, 654. https://doi.org/ 10.3390/pharmaceutics15020654, pp. 1-16.

8. Langel,Ü., Ed. (2022) Cell-penetrating peptides. Methods and protocols, Methods in Molecular Biology, 2383, 3rd ed., Űlo Langel, Editor, ISSN 1064-3745, ISSN 1940-6029 (electronic), https://doi.org/10.1007/978-1-0716-1752-6

9. Langel,Ü. (2023) CPP, Cell-Penetrating Peptides, second edition. Springer Nature Singapore Pte Ltd.,  ISBN 978-3-031-38730-2; ISBN 978-3-031-38731-9 (eBook); https://doi.org/10.1007/978-3-031-38731-9

10. Pirhaghi,M., Mamashli,F., Moosavi-Movahedi,F., Arghavani,P., Amiri,A., Davaeil,B., Mohammad-Zaheri,M., Moosavi-Jarrahi,Z., Langel,Ü., Sharma,D., Otzen,D.E., Saboury,A.A. (2024) Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases. Molecular Pharmaceutics, https://doi.org/10.1021/acs.molpharmaceut.3c01167.

 

Publikationer

I urval från Stockholms universitets publikationsdatabas

  • Cell-penetrating peptides recruit type A scavenger receptors to the plasma membrane for cellular delivery of nucleic acids

    2017. Carmen Juks (et al.). The FASEB Journal 31 (3), 975-988

    Artikel

    Scavenger receptors (SRs) are a large family of multifunctional receptors that are involved in a range of physiologic and pathologic processes. The ability of class A scavenger receptors (SR-As) to bind anionic ligands facilitates the internalization of negatively charged cell-penetrating peptide (CPP)-nucleic acid nanocomplexes and thus makes them attractive targets for delivery of various nucleic acids. Recently, we demonstrated that SR-A3 and SR-A5 are recruited from intracellular membranes to the plasma membrane after incubation with PepFect 14-splice-switching oligonucleotide complexes. Here, we examined the mechanisms responsible for translocation of SR-As to the cell surface. We demonstrate that, in addition to nanocomplexes, some amphipathic CPPs are able to induce externalization of SR-A3 and SR-A5, and this process requires the presence of calcium ions. Furthermore, translocation of SR-A3 and SR-A5 requires activity of phosphatidylinositol-3-kinase, intact actin cytoskeleton, and the presence of serum proteins in culture medium.

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  • Effect of a Fusion Peptide by Covalent Conjugation of a Mitochondrial Cell-Penetrating Peptide and a Glutathione Analog Peptide

    2017. Carmine Pasquale Cerrato, Ülo Langel. Molecular therapy. Methods & clinical development 5, 221-231

    Artikel

    Previously, we designed and synthesized a library of mitochondrial antioxidative cell-penetrating peptides (mtCPPs) superior to the parent peptide, SS31, to protect mitochondria from oxidative damage. A library of antioxidative glutathione analogs called glutathione peptides (UPFs), exceptional in hydroxyl radical elimination compared with glutathione, were also designed and synthesized. Here, a follow-up study is described, investigating the effects of the most promising members from both libraries on reactive oxidative species scavenging ability. None of the peptides influenced cell viability at the concentrations used. Fluorescence microscopy studies showed that the fluorescein-mtCPP1-UPF25 (mtgCPP) internalized into cells, and spectrofluorometric analysis determined the presence and extent of peptide into different cell compartments. mtgCPP has superior antioxidative activity compared with mtCPP1 and UPF25 against H2O2 insult, preventing ROS formation by 2- and 3-fold, respectively. Moreover, we neither observed effects on mitochondrial membrane potential nor production of ATP. These data indicate that mtgCPP is targeting mitochondria, protecting them from oxidative damage, while also being present in the cytosol. Our hypothesis is based on a synergistic effect resulting from the fused peptide. The mitochondrial peptide segment is targeting mitochondria, whereas the glutathione analog peptide segment is active in the cytosol, resulting in increased scavenging ability.

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  • Graphene oxide nanosheets in complex with cell penetrating peptides for oligonucleotides delivery

    2017. Moataz Dowaidar (et al.). Biochimica et Biophysica Acta - General Subjects 1861 (9), 2334-2341

    Artikel

    A new strategy for gene transfection using the nanocarrier of cell penetrating peptides (CPPs; PepFect14 (PF14) or PepFect14 (PF14) (PF221)) in complex with graphene oxide (GO) is reported. GO complexed with CPPs and plasmid (pGL3), splice correction oligonucleotides (SCO) or small interfering RNA (siRNA) are performed. Data show adsorption of CPPs and oligonucleotides on the top of the graphenic lamellar without any observed change of the particle size of GO. GO mitigates the cytotoxicity of CPPs and improves the material biocompatibility. Complexes of GO-pGL3-CPPs (CPPs; PF14 or PF221) offer 2.1–2.5 fold increase of the cell transfection compared to pGL3-CPPs (CPPs; PF14 or PF221). GO-SCO-PF14 assemblies effectively transfect the cells with an increase of > 10–25 fold compared to the transfection using PF14. The concentration of GO plays a significant role in the material nanotoxicity and the transfection efficiency. The results open a new horizon in the gene treatment using CPPs and offer a simple strategy for further investigations.

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  • Magnetic Nanoparticle Assisted Self-assembly of Cell Penetrating Peptides-Oligonucleotides Complexes for Gene Delivery

    2017. Moataz Dowaidar (et al.). Scientific Reports 7

    Artikel

    Magnetic nanoparticles (MNPs, Fe3O4) incorporated into the complexes of cell penetrating peptides (CPPs)-oligonucleotides (ONs) promoted the cell transfection for plasmid transfection, splice correction, and gene silencing efficiencies. Six types of cell penetrating peptides (CPPs; PeptFect220 (denoted PF220), PF221, PF222, PF223, PF224 and PF14) and three types of gene therapeutic agents (plasmid (pGL3), splicing correcting oligonucleotides (SCO), and small interfering RNA (siRNA) were investigated. Magnetic nanoparticles incorporated into the complexes of CPPs-pGL3, CPPs-SCO, and CPPs-siRNA showed high cell biocompatibility and efficiently transfected the investigated cells with pGL3, SCO, and siRNA, respectively. Gene transfer vectors formed among PF14, SCO, and MNPs (PF14-SCO-MNPs) showed a superior transfection efficiency (up to 4-fold) compared to the noncovalent PF14-SCO complex, which was previously reported with a higher efficiency compared to commercial vector called Lipofectamine™2000. The high transfection efficiency of the new complexes (CPPs-SCO-MNPs) may be attributed to the morphology, low cytotoxicity, and the synergistic effect of MNPs and CPPs. PF14-pDNA-MNPs is an efficient complex for in vivo gene delivery upon systemic administration. The conjugation of CPPs-ONs with inorganic magnetic nanoparticles (Fe3O4) may open new venues for selective and efficient gene therapy.

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  • Refinement of a Quantitative Structure–Activity Relationship Model for Prediction of Cell-Penetrating Peptide Based Transfection Systems

    2017. Moataz Dowaidar (et al.). International Journal of Peptide Research and Therapeutics 23 (1), 91-100

    Artikel

    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.

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  • Role of autophagy in PepFect14 transfection

    2017. Moataz Dowaidar (et al.).

    Cell-penetrating peptides (CPP) uptake mechanism is still to be clarified to have a better understanding of their action in the mediation of oligonucleotide transfection. In this study, the effect on early events (1 h treatment) in transfection by Pepfect 14, with or without oligonucleotide cargo on gene expression, on HeLa cells, have been investigated. The RNA expression profile was characterized by RNA sequencing and confirmed with qPCR analysis. The gene regulations were then related to the biological process by the study of signaling pathways that showed the induction of autophagy-related genes in early transfection. A ligand library interfering with the detected intracellular pathways showed concentration-dependent effects on the transfection of splice correction oligonucleotide complexed with Pepfect 14 confirming the induction of autophagy process by the uptake of complexes. Finally, colocalization of nucleic acid cargo and autophagosomes, as well as the autophagosome production induced by the treatment, have been shown by confocal microscopy and transmission electron microscopy. We conclude that autophagy is an important response process triggered by the cellular uptake of CPP-based transfection system. This conclusion opens a possibility to use autophagy modifiers in future gene therapy.

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  • The Formation of Nanoparticles between Small Interfering RNA and Amphipathic Cell-Penetrating Peptides

    2017. Ly Paernaste (et al.). Molecular Therapy - Nucleic Acids 7, 1-10

    Artikel

    Cell-penetrating peptides (CPPs) are delivery vectors widely used to aid the transport of biologically active cargoes to intracellular targets. These cargoes include small interfering RNAs (siRNA) that are not naturally internalized by cells. Elucidating the complexities behind the formation of CPP and cargo complexes is crucial for understanding the processes related to their delivery. In this study, we used modified analogs of the CPP transportan10 and investigated the binding properties of these CPPs to siRNA, the formation parameters of the CPP/siRNA complexes, and their stabiliy to enzymatic degradation. We conclude that the pH dependent change of the net charge of the CPP may very well be the key factor leading to the high delivery efficiency and the optimal binding strength between CPPs to siRNAs, while the hydrophobicity, secondary structure of the CPP, and the positions of the positive charges are responsible for the stability of the CPP/siRNA particles. Also, CPPs with distinct hydrophobic and hydrophilic regions may assemble into nanoparticles that could be described as coreshell formulations.

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