scholarly journals TAT for Enzyme/Protein Delivery to Restore or Destroy Cell Activity in Human Diseases

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 924
Author(s):  
Michal Lichtenstein ◽  
Samar Zabit ◽  
Noa Hauser ◽  
Sarah Farouz ◽  
Orly Melloul ◽  
...  
Keyword(s):  
Protein Delivery ◽  
Cell Activity ◽  
Mitochondrial Diseases ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
Human Diseases ◽  
Enzyme Protein ◽  
Novel Protein ◽  
Cellular Organelles ◽  
Protein Enzyme

Much effort has been dedicated in the recent decades to find novel protein/enzyme-based therapies for human diseases, the major challenge of such therapies being the intracellular delivery and reaching sub-cellular organelles. One promising approach is the use of cell-penetrating peptides (CPPs) for delivering enzymes/proteins into cells. In this review, we describe the potential therapeutic usages of CPPs (mainly trans-activator of transcription protein, TAT) in enabling the uptake of biologically active proteins/enzymes needed in cases of protein/enzyme deficiency, concentrating on mitochondrial diseases and on the import of enzymes or peptides in order to destroy pathogenic cells, focusing on cancer cells.

Direct protein delivery into intact plant cells using polyhistidine peptides

2021 ◽  
Author(s):  
Yoshino Tanaka ◽  
Yoshihiko Nanasato ◽  
Kousei Omura ◽  
Keita Endoh ◽  
Tsuyoshi Kawano ◽  
...  
Keyword(s):  
Cell Lines ◽  
Fusion Proteins ◽  
Protein Delivery ◽  
Fluorescent Protein ◽  
Cultured Cells ◽  
Plant Cells ◽  
Adenosine Monophosphate ◽  
Cell Penetrating Peptides ◽  
Intracellular Space ◽  
Intracellular Fluorescence

Abstract Polyhistidine peptides (PHPs), sequences comprising only histidine residues (>His8), are effective cell-penetrating peptides for plant cells. Using PHP-fusion proteins, we aimed to deliver proteins into cultured plant cells from Nicotiana tabacum, Oryza sativa, and Cryptomeria japonica. Co-cultivation of cultured cells with fusion proteins combining maltose-binding protein (MBP), red fluorescent protein (RFP), and various PHPs (MBP-RFP-His8–His20) in one polypeptide showed the cellular uptake of fusion proteins in all plant cell lines. Maximum intracellular fluorescence was shown in MBP-RFP-His20. Further, adenylate cyclase (CyaA), a synthase of cyclic adenosine monophosphate (cAMP) activated by cytosolic calmodulin, was used as a reporter for protein delivery in living cells. A fusion protein combining MBP, RFP, CyaA, and His20 (MBP-RFP-CyaA-His20) was delivered into plant cells and increased intracellular fluorescence and cAMP production in all cell lines. The present study demonstrates that PHPs are effective carriers of proteins into the intracellular space of various cultured plant cells.

scholarly journals Cell-Penetrating Peptide and siRNA-Mediated Therapeutic Effects on Endometriosis and Cancer In Vitro Models

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1618
Author(s):  
Kristina Kiisholts ◽  
Kaido Kurrikoff ◽  
Piret Arukuusk ◽  
Ly Porosk ◽  
Maire Peters ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cellular Proliferation ◽  
Expression Patterns ◽  
In Vitro Models ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
Therapeutic Effects ◽  
Cell Penetrating ◽  
Proliferation And Invasion

Gene therapy is a powerful tool for the development of new treatment strategies for various conditions, by aiming to transport biologically active nucleic acids into diseased cells. To achieve that goal, we used highly potential delivery vectors, cell-penetrating peptides (CPPs), as oligonucleotide carriers for the development of a therapeutic approach for endometriosis and cancer. Despite marked differences, both of these conditions still exhibit similarities, like excessive, uncoordinated, and autonomous cellular proliferation and invasion, accompanied by overlapping gene expression patterns. Thus, in the current study, we investigated the therapeutic effects of CPP and siRNA nanoparticles using in vitro models of benign endometriosis and malignant glioblastoma. We demonstrated that CPPs PepFect6 and NickFect70 are highly effective in transfecting cell lines, primary cell cultures, and three-dimensional spheroids. CPP nanoparticles are capable of inducing siRNA-specific knockdown of therapeutic genes, ribonucleotide reductase subunit M2 (RRM2), and vascular endothelial growth factor (VEGF), which results in the reduction of in vitro cellular proliferation, invasion, and migration. In addition, we proved that it is possible to achieve synergistic suppression of endometriosis cellular proliferation and invasion by combining gene therapy and hormonal treatment approaches by co-administering CPP/siRNA nanoparticles together with the endometriosis-drug danazol. We suggest a novel target, RRM2, for endometriosis therapy and as a proof-of-concept, we propose a CPP-mediated gene therapy approach for endometriosis and cancer.

scholarly journals Developments in Cell-Penetrating Peptides as Antiviral Agents and as Vehicles for Delivery of Peptide Nucleic Acid Targeting Hepadnaviral Replication Pathway

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 55 ◽  
Author(s):  
Bénédicte Ndeboko ◽  
Olivier Hantz ◽  
Guy Lemamy ◽  
Lucyna Cova
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Infection Model ◽  
Sequence Specificity ◽  
Chronic Hepatitis B Virus

Alternative therapeutic approaches against chronic hepatitis B virus (HBV) infection need to be urgently developed because current therapies are only virostatic. In this context, cell penetration peptides (CPPs) and their Peptide Nucleic Acids (PNAs) cargoes appear as a promising novel class of biologically active compounds. In this review we summarize different in vitro and in vivo studies, exploring the potential of CPPs as vehicles for intracellular delivery of PNAs targeting hepadnaviral replication. Thus, studies conducted in the duck HBV (DHBV) infection model showed that conjugation of (D-Arg)8 CPP to PNA targeting viral epsilon (ε) were able to efficiently inhibit viral replication in vivo following intravenous administration to ducklings. Unexpectedly, some CPPs, (D-Arg)8 and Decanoyl-(D-Arg)8, alone displayed potent antiviral effect, altering late stages of DHBV and HBV morphogenesis. Such antiviral effects of CPPs may affect the sequence-specificity of CPP-PNA conjugates. By contrast, PNA conjugated to (D-Lys)4 inhibited hepadnaviral replication without compromising sequence specificity. Interestingly, Lactose-modified CPP mediated the delivery of anti-HBV PNA to human hepatoma cells HepaRG, thus improving its antiviral activity. In light of these promising data, we believe that future studies will open new perspectives for translation of CPPs and CPP-PNA based technology to therapy of chronic hepatitis B.

scholarly journals Cellular Reprogramming Employing Recombinant Sox2 Protein

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Marc Thier ◽  
Bernhard Münst ◽  
Stephanie Mielke ◽  
Frank Edenhofer
Keyword(s):  
Protein Delivery ◽  
Disease Modeling ◽  
Ips Cells ◽  
Cellular Reprogramming ◽  
Protein Stabilization ◽  
Biologically Active ◽  
Patient Specific ◽  
Tat Protein ◽  
Serum Replacement ◽  
Induced Pluripotent

Induced pluripotent stem (iPS) cells represent an attractive option for the derivation of patient-specific pluripotent cells for cell replacement therapies as well as disease modeling. To become clinically meaningful, safe iPS cells need to be generated exhibiting no permanent genetic modifications that are caused by viral integrations of the reprogramming transgenes. Recently, various experimental strategies have been applied to accomplish transgene-free derivation of iPS cells, including the use of nonintegrating viruses, episomal expression, or excision of transgenes after reprogramming by site-specific recombinases or transposases. A straightforward approach to induce reprogramming factors is the direct delivery of either synthetic mRNA or biologically active proteins. We previously reported the generation of cell-permeant versions of Oct4 (Oct4-TAT) and Sox2 (Sox2-TAT) proteins and showed that Oct4-TAT is reprogramming-competent, that is, it can substitute for Oct4-encoding virus. Here, we explore conditions for enhanced Sox2-TAT protein stabilization and functional delivery into somatic cells. We show that cell-permeant Sox2 protein can be stabilized by lipid-rich albumin supplements in serum replacement or low-serum-supplemented media. Employing optimized conditions for protein delivery, we demonstrate that Sox2-TAT protein is able to substitute for viral Sox2. Sox2-piPS cells express pluripotency-associated markers and differentiate into all three germ layers.

scholarly journals Functional Interplay between Cristae Biogenesis, Mitochondrial Dynamics and Mitochondrial DNA Integrity

2019 ◽  
Vol 20 (17) ◽  
pp. 4311 ◽  
Author(s):  
Arun Kumar Kondadi ◽  
Ruchika Anand ◽  
Andreas S. Reichert
Keyword(s):  
Mitochondrial Dna ◽  
Unique Feature ◽  
Mitochondrial Dynamics ◽  
Human Diseases ◽  
Dna Integrity ◽  
Cellular Processes ◽  
The Past ◽  
Mitochondrial Structure ◽  
Mitochondrial Functions ◽  
Cellular Organelles

Mitochondria are vital cellular organelles involved in a plethora of cellular processes such as energy conversion, calcium homeostasis, heme biogenesis, regulation of apoptosis and ROS reactive oxygen species (ROS) production. Although they are frequently depicted as static bean-shaped structures, our view has markedly changed over the past few decades as many studies have revealed a remarkable dynamicity of mitochondrial shapes and sizes both at the cellular and intra-mitochondrial levels. Aberrant changes in mitochondrial dynamics and cristae structure are associated with ageing and numerous human diseases (e.g., cancer, diabetes, various neurodegenerative diseases, types of neuro- and myopathies). Another unique feature of mitochondria is that they harbor their own genome, the mitochondrial DNA (mtDNA). MtDNA exists in several hundreds to thousands of copies per cell and is arranged and packaged in the mitochondrial matrix in structures termed mt-nucleoids. Many human diseases are mechanistically linked to mitochondrial dysfunction and alteration of the number and/or the integrity of mtDNA. In particular, several recent studies identified remarkable and partly unexpected links between mitochondrial structure, fusion and fission dynamics, and mtDNA. In this review, we will provide an overview about these recent insights and aim to clarify how mitochondrial dynamics, cristae ultrastructure and mtDNA structure influence each other and determine mitochondrial functions.

scholarly journals Antibody Mediated Transduction of Therapeutic Proteins into Living Cells

2005 ◽  
Vol 5 ◽  
pp. 782-788 ◽  
Author(s):  
James E. Hansen ◽  
Richard H. Weisbart ◽  
Robert N. Nishimura
Keyword(s):  
Therapeutic Proteins ◽  
Disease Process ◽  
Antibody Fragment ◽  
Living Cells ◽  
Cell Penetrating Peptides ◽  
Biologically Active ◽  
Protein Transduction ◽  
Protein Therapy ◽  
Single Chain ◽  
Protein Transduction Domains

Protein therapy refers to the direct delivery of therapeutic proteins to cells and tissues with the goal of ameliorating or modifying a disease process. Current techniques for delivering proteins across cell membranes include taking advantage of receptor-mediated endocytosis or using protein transduction domains that penetrate directly into cells. The most commonly used protein transduction domains are small cell-penetrating peptides derived from such proteins as the HIV-1 Tat protein. A novel protein transduction domain developed as the single chain fragment (Fv) of a murine anti-DNA autoantibody, mAb 3E10, has recently been developed and used to deliver biologically active proteins to living cellsin vitro. This review will provide a brief overview of the development of the Fv fragment and provide a summary of recent studies using Fv to deliver therapeutic peptides and proteins (such as a C-terminal p53 peptide, C-terminal p53 antibody fragment, full-length p53, and micro-dystrophin) to cells.

scholarly journals Dissecting the Translocase and Integrase Functions of the Escherichia coli Secyeg Translocon

2000 ◽  
Vol 150 (3) ◽  
pp. 689-694 ◽  
Author(s):  
Hans-Georg Koch ◽  
Matthias Müller
Keyword(s):  
Escherichia Coli ◽  
Membrane Proteins ◽  
Protein Delivery ◽  
Signal Recognition Particle ◽  
Membrane Vesicles ◽  
Biologically Active ◽  
Secretory Proteins ◽  
Signal Recognition ◽  
Inner Membrane ◽  
Independent Protein

Recent evidence suggests that in Escherichia coli, SecA/SecB and signal recognition particle (SRP) are constituents of two different pathways targeting secretory and inner membrane proteins to the SecYEG translocon of the plasma membrane. We now show that a secY mutation, which compromises a functional SecY–SecA interaction, does not impair the SRP-mediated integration of polytopic inner membrane proteins. Furthermore, under conditions in which the translocation of secretory proteins is strictly dependent on SecG for assisting SecA, the absence of SecG still allows polytopic membrane proteins to integrate at the wild-type level. These results indicate that SRP-dependent integration and SecA/SecB-mediated translocation do not only represent two independent protein delivery systems, but also remain mechanistically distinct processes even at the level of the membrane where they engage different domains of SecY and different components of the translocon. In addition, the experimental setup used here enabled us to demonstrate that SRP-dependent integration of a multispanning protein into membrane vesicles leads to a biologically active enzyme.

scholarly journals Revealing the Therapeutic Uses of Garlic (Allium sativum) and Its Potential for Drug Discovery

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Azene Tesfaye
Keyword(s):  
Drug Development ◽  
Therapeutic Potential ◽  
Biologically Active ◽  
Human Diseases ◽  
Active Components ◽  
Runny Nose ◽  
Medicinal Value ◽  
Therapeutic Uses ◽  
Tract Disease ◽  
Chronic Fever

Background. Garlic is a common bulb vegetable that is used to flavor and flavor food. The plant contains biologically active components that contribute to its pharmacological properties. This paper attempts to examine the therapeutic uses and potential role in the drug development of garlic for various human diseases. Methods. To obtain crucial data and scientific knowledge about the therapeutic uses of garlic, systematic literature searches were conducted using key terms on well-known indexed platforms such as PubMed, Scopus, Web of Science, Medline, Embase, and popular search engines. Results. Garlic, which is utilized as a spice and flavoring ingredient, is found to have fundamental nutritional components. Carbohydrates, protein, fat, minerals, water, and vitamins are all found in abundance in this plant. The plant also has a high medicinal value and is used to cure a variety of human diseases. It has anti-inflammatory, rheumatological, ulcer inhibiting, anticholinergic, analgesic, antimicrobial, antistress, antidiabetes, anticancer, liver protection, anthelmintics, antioxidants, antifungal, and wound healing properties, as well as properties that help with asthma, arthritis, chronic fever, tuberculosis, runny nose, malaria, leprosy, skin discoloration, and itching, indigestion, colic, enlarged spleen, hemorrhoids, fistula, bone fracture, gout, urinary tract disease, diabetes, kidney stones, anemia, jaundice, epilepsy, cataract, and night blindness. Conclusions. The nutritional content of the plant is significant, and it has incredible therapeutic potential. The findings of this study are needed to investigate the therapeutic potential, as it may be a promising option for drug development.

scholarly journals Cyclopentenone Prostaglandins: Biologically Active Lipid Mediators Targeting Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Bohae Rachel Lee ◽  
May Hnin Paing ◽  
Neelam Sharma-Walia
Keyword(s):  
Viral Protein ◽  
Parasitic Infection ◽  
Cell Activity ◽  
Lipid Mediators ◽  
Protein Glycosylation ◽  
Biologically Active ◽  
Peroxisome Proliferator ◽  
Viral Protein Synthesis ◽  
Ppar Γ ◽  
Cyclopentenone Prostaglandins

Cyclopentenone prostaglandins (cyPGs) are biologically active lipid mediators, including PGA2, PGA1, PGJ2, and its metabolites. cyPGs are essential regulators of inflammation, cell proliferation, apoptosis, angiogenesis, cell migration, and stem cell activity. cyPGs biologically act on multiple cellular targets, including transcription factors and signal transduction pathways. cyPGs regulate the inflammatory response by interfering with NF-κB, AP-1, MAPK, and JAK/STAT signaling pathways via both a group of nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-γ) dependent and PPAR-γ independent mechanisms. cyPGs promote the resolution of chronic inflammation associated with cancers and pathogen (bacterial, viral, and parasitic) infection. cyPGs exhibit potent effects on viral infections by repressing viral protein synthesis, altering viral protein glycosylation, inhibiting virus transmission, and reducing virus-induced inflammation. We summarize their anti-proliferative, pro-apoptotic, cytoprotective, antioxidant, anti-angiogenic, anti-inflammatory, pro-resolution, and anti-metastatic potential. These properties render them unique therapeutic value, especially in resolving inflammation and could be used in adjunct with other existing therapies. We also discuss other α, β -unsaturated carbonyl lipids and cyPGs like isoprostanes (IsoPs) compounds.

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