Bifunctional peptide hybrids targeting the matrix of mitochondria

Klimpel, Annika; Neundorf, Ines

doi:10.1016/j.jconrel.2018.10.029

Cited by 45 publications

(21 citation statements)

References 43 publications

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“…Notably, the averaged fluorescence intensity measured for CF‐sC18‐I‐Pc was about 900 % higher than for CF‐sC18 (Figure C) which is in accordance with results from microscopic uptake studies (Figures S2A and S2C, respectively). In previous work, we have demonstrated that sC18 as well as a truncated version named sC18* are able to induce and stabilize helix formation, when attached to peptide sequences . The presence of such helical structures is very important for the peptide–lipid interaction at the plasma membrane surface, and thus, these peptide hybrids are often characterized by increased cellular uptake and biological activity in comparison to sC18 alone.…”

Section: Resultsmentioning

confidence: 99%

“…In previous work, we have demonstrated that sC18 as well as at runcated version named sC18* are able to induce and stabilize helix formation, when attached to peptide sequences. [42,[56][57][58] The presenceo fs uch helical structures is very important for the peptide-lipid interaction at the plasma membrane surface, and thus, thesep eptideh ybrids are often characterized by increased cellular uptake and biological activity in comparison to sC18 alone. In the absence of sC18, as in CF-Ahx-Pc, peptide internalization into cells is almost abolished ( Figure S2B).…”

Section: Synthesis Of Pc Derivatives and Characterization With Human mentioning

confidence: 99%

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Design of CK2β‐Mimicking Peptides as Tools To Study the CK2α/CK2β Interaction in Cancer Cells

et al. 2019

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The ubiquitously expressed Ser/Thr kinase CK2 is a key regulator in a variety of key processes in normal and malignant cells. Due to its distinctive anti‐apoptotic and tumor‐driving properties, elevated levels of CK2 have frequently been found in tumors of different origin. In recent years, development of CK2 inhibitors has largely been focused on ATP‐competitive compounds; however, targeting the CK2α/CK2β interface has emerged as a further concept that might avoid selectivity issues. To address the CK2 subunit interaction site, we have synthesized halogenated CK2β‐mimicking cyclic peptides modified with the cell‐penetrating peptide sC18 to mediate cellular uptake. We investigated the binding of the resulting chimeric peptides to recombinant human CK2α using a recently developed fluorescence anisotropy assay. The iodinated peptide sC18‐I‐Pc was identified as a potent CK2α ligand (Ki=0.622 μm). It was internalized in cells to a high extent and exhibited significant cytotoxicity toward cancerous HeLa cells (IC50=37 μm) in contrast to non‐cancerous HEK‐293 cells. The attractive features and functionalities of sC18‐I‐Pc offer the opportunity for further improvement.

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Pc Derivatives and Characterization With Human mentioning

confidence: 99%

Design of CK2β‐Mimicking Peptides as Tools To Study the CK2α/CK2β Interaction in Cancer Cells

et al. 2019

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“…In recent work, we developed sC18 as a very effective transporter for various cargos, e.g. metal organic complexes 29 , cytostatic drugs 30 , or peptides 31 . From our previous studies, we have also recognized that sC18 forms an amphipathic alpha-helical structure when in presence of a lipid environment 30 .…”

Section: Introductionmentioning

confidence: 99%

Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity

Drexelius

Reinhardt

Grabeck

et al. 2021

Biochemical Journal

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Multidrug resistant (MDR) bacteria have adapted to most clinical antibiotics and are a growing threat to human health. One promising type of candidates for the everlasting demand of new antibiotic compounds constitute antimicrobial peptides (AMPs). These peptides act against different types of microbes by permeabilizing pathogen cell membranes, whereas being harmless to mammalian cells. Contrarily, another class of membrane-active peptides, namely cell-penetrating peptides (CPPs), is known to translocate in eukaryotic cells without substantially affecting the cell membrane. Since CPPs and AMPs share several physicochemical characteristics, we hypothesized if we can rationally direct the activity of a CPP towards antimicrobial activity. Herein, we describe the screening of a synthetic library, based on the CPP sC18, including structure-based design to identify the active residues within a CPP sequence and to discover novel AMPs with high activity. Peptides with increased hydrophobicity were tested against various bacterial strains, and hits were further optimized leading to four generations of peptides, with the last also comprising fluorinated amino acid building blocks. Interestingly, beside strong antibacterial activities, we also detected activity in cancer cells, while non-cancerous cells remained unharmed. The results highlight our new candidates, particularly those from generation 4, as a valuable and promising source for the development of future therapeutics with antibacterial activity and beyond.

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“…Other reports also confirmed this feasible strategy (Del Gaizo and Mark Payne 2003;Lin et al 2015). Recently, Klimpel et al designed a hybrid peptide composed of CPP sC18 and MTS and found this bifunctional peptide exhibited remarkably promoted cellular uptake and mitochondrial matrix distribution for dozens of times compared to free MTS (Klimpel and Neundorf 2018). Furthermore, MTS-sC18 was proven to efficiently deliver chlorambucil into mitochondria, making it a promising candidate for mitochondrial targeted drug delivery.…”

Section: Mitochondrial Targeting Sequencesmentioning

confidence: 85%

Mitochondrial targeted strategies and their application for cancer and other diseases treatment

Huang

2020

J. Pharm. Investig.

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Background Known as the main site of ATP production and intrinsic apoptosis regulator, mitochondria play vital roles in physiological functions and pathological progression. Evidences have shown that mitochondrial dysfunction correlated with a variety of diseases, especially with cancer. Mitochondria are emerged as an attractive target for diseases treatment. Area covered This review introduces efficient mitochondrial targeting strategies, and summarizes application of multiple drug delivery systems targeted to mitochondria for antitumor treatment, including anti-drug resistance, anti-metastasis and immunotherapy. Furthermore, we discuss the application and perspectives of mitochondrial targeting in treatment of other mitochondrial-related diseases. Expert opinion A number of chemotherapeutics exert their efficacy in specific sub-organelles. Targeting drugs to one certain organelle would exhibit their maximum therapeutic effects. The mitochondria in tumor cells are closely related to the development of tumor. Also, the main cause of clinical failure in antitumor treatment, including multidrug resistance (MDR) and metastasis, are associated with mitochondrial dysfunction. In addition, mitochondria disorders also lead to some other diseases. Therefore, constructing mitochondrial targeted drug delivery systems to regulate mitochondrial functions is necessarily desired.

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Bifunctional peptide hybrids targeting the matrix of mitochondria

Cited by 45 publications

References 43 publications

Design of CK2β‐Mimicking Peptides as Tools To Study the CK2α/CK2β Interaction in Cancer Cells

Design of CK2β‐Mimicking Peptides as Tools To Study the CK2α/CK2β Interaction in Cancer Cells

Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity

Mitochondrial targeted strategies and their application for cancer and other diseases treatment

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