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Pirhaghi, M., Mamashli, F., Moosavi-Movahedi, F., Arghavani, P., Amiri, A., Davaeil, B., . . . Saboury, A. A. (2024). Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases. Molecular Pharmaceutics
Open this publication in new window or tab >>Cell-Penetrating Peptides: Promising Therapeutics and Drug-Delivery Systems for Neurodegenerative Diseases
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2024 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392Article, review/survey (Refereed) Epub ahead of print
Abstract [en]

Currently, one of the most significant and rapidly growing unmet medical challenges is the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This challenge encompasses the imperative development of efficacious therapeutic agents and overcoming the intricacies of the blood-brain barrier for successful drug delivery. Here we focus on the delivery aspect with particular emphasis on cell-penetrating peptides (CPPs), widely used in basic and translational research as they enhance drug delivery to challenging targets such as tissue and cellular compartments and thus increase therapeutic efficacy. The combination of CPPs with nanomaterials such as nanoparticles (NPs) improves the performance, accuracy, and stability of drug delivery and enables higher drug loads. Our review presents and discusses research that utilizes CPPs, either alone or in conjugation with NPs, to mitigate the pathogenic effects of neurodegenerative diseases with particular reference to AD and PD.

Keywords
cell-penetrating peptides, central nervous system disorders, peptide-nanoparticleconjugate, drug delivery, Alzheimer's disease(AD), Parkinson's disease(PD)
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:su:diva-228247 (URN)10.1021/acs.molpharmaceut.3c01167 (DOI)001180303800001 ()38440998 (PubMedID)2-s2.0-85187010218 (Scopus ID)
Available from: 2024-04-11 Created: 2024-04-11 Last updated: 2024-04-11
Nebogatova, J., Hark, H. H., Puskar, A., Porosk, L., Guazzi, P., Dowaidar, M., . . . Kurrikoff, K. (2023). A Method for Using Cell-Penetrating Peptides for Loading Plasmid DNA into Secreted Extracellular Vesicles. Biomolecules, 13(12), Article ID 1751.
Open this publication in new window or tab >>A Method for Using Cell-Penetrating Peptides for Loading Plasmid DNA into Secreted Extracellular Vesicles
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2023 (English)In: Biomolecules, E-ISSN 2218-273X, Vol. 13, no 12, article id 1751Article in journal (Refereed) Published
Abstract [en]

The low bioavailability and high toxicity of plasmid DNA (pDNA)-based therapeutics pose challenges for their in vivo application. Extracellular vesicles (EVs) have great potential to overcome these limitations, as they are biocompatible native cargo carriers. Various methods for loading pDNA into EVs, including electroporation, sonication, and co-incubation, have been previously investigated, but their success has been questionable. In this study, we report a unique method for loading EVs with pDNA through transient transfection using cell-penetrating peptides (CPPs). With this method, we found a 104-fold increase in the expression levels of the luciferase reporter protein in recipient cells compared to the untreated cells. These data point to the high transfection efficacy and bioavailability of the delivered encapsulated nucleic acid. Furthermore, the in vivo experimental data indicate that the use of pDNA-loaded EVs as native delivery vehicles reduces the toxic effects associated with traditional nucleic acid (NA) delivery and treatment.

Keywords
extracellular vesicles, gene therapy, nucleic acid therapeutics, drug delivery system, cell-penetrating peptides
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-225804 (URN)10.3390/biom13121751 (DOI)001131235100001 ()38136622 (PubMedID)2-s2.0-85180712095 (Scopus ID)
Available from: 2024-01-23 Created: 2024-01-23 Last updated: 2024-01-23Bibliographically approved
Porosk, L., Härk, H. H., Bicev, R. N., Gaidutšik, I., Nebogatova, J., Armolik, E.-J., . . . Langel, Ü. (2023). Aggregation Limiting Cell-Penetrating Peptides Derived from Protein Signal Sequences. International Journal of Molecular Sciences, 24(5), Article ID 4277.
Open this publication in new window or tab >>Aggregation Limiting Cell-Penetrating Peptides Derived from Protein Signal Sequences
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2023 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 5, article id 4277Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is the most common neurodegenerative disease (ND) and the leading cause of dementia. It is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in the biological alterations and the causes of the disease. One of the hallmarks of the AD is the progression of plaques of aggregated amyloid-β (Aβ) or neurofibrillary tangles of Tau. Currently there is no efficient treatment for the AD. Nevertheless, several breakthroughs in revealing the mechanisms behind progression of the AD have led to the discovery of possible therapeutic targets. Some of these include the reduction in inflammation in the brain, and, although highly debated, limiting of the aggregation of the Aβ. In this work we show that similarly to the Neural cell adhesion molecule 1 (NCAM1) signal sequence, other Aβ interacting protein sequences, especially derived from Transthyretin, can be used successfully to reduce or target the amyloid aggregation/aggregates in vitro. The modified signal peptides with cell-penetrating properties reduce the Aβ aggregation and are predicted to have anti-inflammatory properties. Furthermore, we show that by expressing the Aβ-EGFP fusion protein, we can efficiently assess the potential for reduction in aggregation, and the CPP properties of peptides in mammalian cells.

Keywords
amyloid beta, cell-penetrating peptides, Alzheimer's disease, aggregation, peptides
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:su:diva-215997 (URN)10.3390/ijms24054277 (DOI)000948285400001 ()36901707 (PubMedID)2-s2.0-85149977484 (Scopus ID)
Available from: 2023-04-03 Created: 2023-04-03 Last updated: 2023-04-03Bibliographically approved
Saldanha, L., Langel, Ü. & Vale, N. (2023). In Silico Studies to Support Vaccine Development. Pharmaceutics, 15(2), Article ID 654.
Open this publication in new window or tab >>In Silico Studies to Support Vaccine Development
2023 (English)In: Pharmaceutics, E-ISSN 1999-4923, Vol. 15, no 2, article id 654Article in journal (Refereed) Published
Abstract [en]

The progress that has been made in computer science positioned in silico studies as an important and well-recognized methodology in the drug discovery and development process. It has numerous advantages in terms of costs and also plays a huge impact on the way the research is conducted since it can limit the use of animal models leading to more sustainable research. Currently, human trials are already being partly replaced by in silico trials. EMA and FDA are both endorsing these studies and have been providing webinars and guidance to support them. For instance, PBPK modeling studies are being used to gather data on drug interactions with other drugs and are also being used to support clinical and regulatory requirements for the pediatric population, pregnant women, and personalized medicine. This trend evokes the need to understand the role of in silico studies in vaccines, considering the importance that these products achieved during the pandemic and their promising hope in oncology. Vaccines are safer than other current oncology treatments. There is a huge variety of strategies for developing a cancer vaccine, and some of the points that should be considered when designing the vaccine technology are the following: delivery platforms (peptides, lipid-based carriers, polymers, dendritic cells, viral vectors, etc.), adjuvants (to boost and promote inflammation at the delivery site, facilitating immune cell recruitment and activation), choice of the targeted antigen, the timing of vaccination, the manipulation of the tumor environment, and the combination with other treatments that might cause additive or even synergistic anti-tumor effects. These and many other points should be put together to outline the best vaccine design. The aim of this article is to perform a review and comprehensive analysis of the role of in silico studies to support the development of and design of vaccines in the field of oncology and infectious diseases. The authors intend to perform a literature review of all the studies that have been conducted so far in preparing in silico models and methods to support the development of vaccines. From this point, it was possible to conclude that there are few in silico studies on vaccines. Despite this, an overview of how the existing work could support the design of vaccines is described.

Keywords
vaccines, in silico, population pharmacokinetics, PopPK, PBPK, computational
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:su:diva-216015 (URN)10.3390/pharmaceutics15020654 (DOI)000941703100001 ()36839975 (PubMedID)2-s2.0-85149136727 (Scopus ID)
Available from: 2023-03-30 Created: 2023-03-30 Last updated: 2024-07-04Bibliographically approved
Langel, Ü. (2023). Nucleic acid delivery by cell-penetrating peptides. Proceedings of the Estonian Academy of Sciences, 72(4), 361-370
Open this publication in new window or tab >>Nucleic acid delivery by cell-penetrating peptides
2023 (English)In: Proceedings of the Estonian Academy of Sciences, ISSN 1736-6046, E-ISSN 1736-7530, Vol. 72, no 4, p. 361-370Article in journal (Refereed) Published
Abstract [en]

Establishment of multiple novel mechanisms and applications of cell-penetrating peptides (CPP) has been demonstrated, leading to novel drug delivery systems. Here, I present a brief introduction to the CPP area together with the selected recent achievements in the delivery of nucleic acids.

Keywords
cell-penetrating peptides, transfection, transportan, PepFect, NickFect
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-227339 (URN)10.3176/proc.2023.4.01 (DOI)001152072100002 ()
Available from: 2024-03-12 Created: 2024-03-12 Last updated: 2024-03-12Bibliographically approved
Silva, S., Kurrikoff, K., Langel, Ü., Almeida, A. J. & Vale, N. (2022). A Second Life for MAP, a Model Amphipathic Peptide. International Journal of Molecular Sciences, 23(15), Article ID 8322.
Open this publication in new window or tab >>A Second Life for MAP, a Model Amphipathic Peptide
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2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 15, article id 8322Article, review/survey (Refereed) Published
Abstract [en]

Cell-penetrating peptides (CPP) have been shown to be efficient in the transport of cargoes into the cells, namely siRNA and DNA, proteins and peptides, and in some cases, small therapeutics. These peptides have emerged as a solution to increase drug concentrations in different tissues and various cell types, therefore having a relevant therapeutic relevance which led to clinical trials. One of them, MAP, is a model amphipathic peptide with an α-helical conformation and both hydrophilic and hydrophobic residues in opposite sides of the helix. It is composed of a mixture of alanines, leucines, and lysines (KLALKLALKALKAALKLA). The CPP MAP has the ability to translocate oligonucleotides, peptides and small proteins. However, taking advantage of its unique properties, in recent years innovative concepts were developed, such as in silico studies of modelling with receptors, coupling and repurposing drugs in the central nervous system and oncology, or involving the construction of dual-drug delivery systems using nanoparticles. In addition to designs of MAP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy, this review will be focused on unique molecular structure and how it determines its cellular activity, and also intends to address the most recent and frankly motivating issues for the future.

Keywords
model amphipathic peptide, cell-penetrating peptides, delivery system, drug repurposing, CNS, oncology, nanoparticles
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-209422 (URN)10.3390/ijms23158322 (DOI)000839063500001 ()35955457 (PubMedID)2-s2.0-85136342129 (Scopus ID)
Available from: 2022-09-20 Created: 2022-09-20 Last updated: 2022-09-20Bibliographically approved
Kuznetsov, A., Arukuusk, P., Härk, H., Juronen, E., Ustav, M., Langel, Ü. & Järv, J. (2022). ACE2 Peptide Fragment Interaction with Different S1 Protein Sites. International journal of peptide research and therapeutics, 28(1), Article ID 7.
Open this publication in new window or tab >>ACE2 Peptide Fragment Interaction with Different S1 Protein Sites
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2022 (English)In: International journal of peptide research and therapeutics, ISSN 1573-3149, Vol. 28, no 1, article id 7Article in journal (Refereed) Published
Abstract [en]

We study the effect of the peptide QAKTFLDKFNHEAEDLFYQ on the kinetics of the SARS-CoV-2 spike protein S1 binding to angiotensin-converting enzyme 2 (ACE2), with the aim to characterize the interaction mechanism of the SARS-CoV2 virus with its host cell. This peptide corresponds to the sequence 24-42 of the ACE2 alpha 1 domain, which marks the binding site for the S1 protein. The kinetics of S1-ACE2 complex formation was measured in the presence of various concentrations of the peptide using bio-layer interferometry. Formation of the S1-ACE2 complex was inhibited by the peptide in cases where it was preincubated with S1 protein before the binding experiment. The kinetic analysis of S1-ACE2 complex dissociation revealed that preincubation stabilized this complex, and this effect was dependent on the peptide concentration as well as the preincubation time. The results point to the formation of the ternary complex of S1 with ACE2 and the peptide. This is possible in the presence of another binding site for the S1 protein beside the receptor-binding domain for ACE2, which binds the peptide QAKTFLDKFNHEAEDLFYQ. Therefore, we conducted computational mapping of the S1 protein surface, revealing two additional binding sites located at some distance from the main receptor-binding domain on S1. We suggest the possibility to predict and test the short protein derived peptides for development of novel strategies in inhibiting virus infections.

Keywords
Peptide, Bio-layer interferometry, Peptide binding kinetics, SARS-CoV-2 spike protein, ACE2 peptide fragment, Allosteric binding site, Peptide docking
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-200417 (URN)10.1007/s10989-021-10324-7 (DOI)000724791400010 ()34867130 (PubMedID)
Available from: 2022-01-05 Created: 2022-01-05 Last updated: 2022-01-05Bibliographically approved
Cerrato, C. P. & Langel, Ü. (2022). An update on cell-penetrating peptides with intracellular organelle targeting. Expert Opinion on Drug Delivery, 19(2), 133-146
Open this publication in new window or tab >>An update on cell-penetrating peptides with intracellular organelle targeting
2022 (English)In: Expert Opinion on Drug Delivery, ISSN 1742-5247, E-ISSN 1744-7593, Vol. 19, no 2, p. 133-146Article, review/survey (Refereed) Published
Abstract [en]

Introduction Cell-penetrating peptide (CPP) technologies represent an important strategy to address drug delivery to specific intracellular compartments by covalent conjugation to targeting sequences, potentially enabling strategies to combat most diseases.

Areas covered This updated review article provides an overview of current intracellular organelle targeting by CPP. The targeting strategies of CPP and CPP/cargo complexes to specific cells or intracellular organelles are summarized, and the review provides an update on the current data for their pharmacological and therapeutical applications.

Expert opinion Targeted drug delivery is moving from the level of tissue or specific pathogenic cell to the level of specific organelle that is the target of the drug, an important aspect in drug design and development. Organelle-targeted drug delivery results in improved efficacy, ability to control mode of action, reduction of undesired toxicities and side effects, and the possibility to overcome drug resistance mechanisms.

Keywords
Delivery, endoplasmic reticulum, lysosomes, mitochondria, nuclei, organelle, precision medicine, targeting
National Category
Cell and Molecular Biology Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:su:diva-202598 (URN)10.1080/17425247.2022.2034784 (DOI)000753901700001 ()35086398 (PubMedID)2-s2.0-85124873480 (Scopus ID)
Available from: 2022-03-10 Created: 2022-03-10 Last updated: 2022-03-29Bibliographically approved
Porosk, L. & Langel, Ü. (2022). Approaches for evaluation of novel CPP-based cargo delivery systems. Frontiers in Pharmacology, 13, Article ID 1056467.
Open this publication in new window or tab >>Approaches for evaluation of novel CPP-based cargo delivery systems
2022 (English)In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1056467Article, review/survey (Refereed) Published
Abstract [en]

Cell penetrating peptides (CPPs) can be broadly defined as relatively short synthetic, protein derived or chimeric peptides. Their most remarkable property is their ability to cross cell barriers and facilitate the translocation of cargo, such as drugs, nucleic acids, peptides, small molecules, dyes, and many others across the plasma membrane. Over the years there have been several approaches used, adapted, and developed for the evaluation of CPP efficacies as delivery systems, with the fluorophore attachment as the most widely used approach. It has become progressively evident, that the evaluation method, in order to lead to successful outcome, should concede with the specialties of the delivery. For characterization and assessment of CPP-cargo a combination of research tools of chemistry, physics, molecular biology, engineering, and other fields have been applied. In this review, we summarize the diverse, in silico, in vitro and in vivo approaches used for evaluation and characterization of CPP-based cargo delivery systems.

Keywords
cell-penetrating peptides, cargo delivery, transfection, nucleic acid therapeutics, evaluation approaches
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:su:diva-211614 (URN)10.3389/fphar.2022.1056467 (DOI)000879703400001 ()36339538 (PubMedID)2-s2.0-85141409672 (Scopus ID)
Available from: 2022-11-24 Created: 2022-11-24 Last updated: 2024-01-17Bibliographically approved
Zorko, M. & Langel, Ü. (2022). Cell-Penetrating Peptides (3ed.). In: Ülo Langel (Ed.), Cell Penetrating Peptides: Methods and Protocols (pp. 3-32). New York: Humana Press
Open this publication in new window or tab >>Cell-Penetrating Peptides
2022 (English)In: Cell Penetrating Peptides: Methods and Protocols / [ed] Ülo Langel, New York: Humana Press, 2022, 3, p. 3-32Chapter in book (Refereed)
Abstract [en]

In this introductory chapter, we first define cell-penetrating peptides (CPPs), give short overview of CPP history and discuss several aspects of CPP classification. Next section is devoted to the mechanism of CPP penetration into the cells, where direct and endocytic internalization of CPP is explained. Kinetics of internalization is discussed more extensively, since this topic is not discussed in other chapters of this book. At the end of this section some features of the thermodynamics of CPP interaction with the membrane is also presented. Finally, we present different cargoes that can be transferred into the cells by CPPs and briefly discuss the effect of cargo on the rate and efficiency of penetration into the cells. 

Place, publisher, year, edition, pages
New York: Humana Press, 2022 Edition: 3
Series
Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029 ; 2383
Keywords
CPP classes, Mechanisms, Kinetics, Direct translocation, Endocytic uptake
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:su:diva-209856 (URN)10.1007/978-1-0716-1752-6_1 (DOI)34766279 (PubMedID)2-s2.0-85119149025 (Scopus ID)978-1-0716-1751-9 (ISBN)978-1-0716-1752-6 (ISBN)
Available from: 2022-10-03 Created: 2022-10-03 Last updated: 2022-10-03Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6107-0844

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