Conceptually New Entries into Cells

Montenegro, Javier; Gehin, Charlotte; Bang, Eun‐Kyoung; Fin, Andréa; Doval, David Alonso; Riezman, Howard; Sakai, Naomi; Matile, Stefan

doi:10.2533/chimia.2011.853

Cited by 11 publications

(7 citation statements)

References 11 publications

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“…Current efforts focus on the import of more unusual tails such as fullerenes, mesogenes or fluorophiles from the materials sciences to increase the probability to discover unexpected hits, and the growing library is being screened for gene and siRNA delivery. Preliminary results are encouraging, and confirm the construction and screening of expanded libraries of dynamic amphiphiles as a meaningful approach, because the current hits are: 1) competitive with the current delivery agents on the market, 2) unpredictable from model studies in vesicles, and 3) unpredictable from the literature 12a. These results will be reported in due course.…”

Section: Resultsmentioning

confidence: 59%

Synthesis of an Enlarged Library of Dynamic DNA Activators with Oxime, Disulfide and Hydrazone Bridges

Montenegro

Bang

Sakai

et al. 2012

Chemistry A European J

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Dynamic amphiphiles have a "bridge" between their charged head and their hydrophobic tails. The presence of dynamic covalent bonds is of interest for differential and biosensing applications as well as for rapid access to the libraries needed to screen for gene delivery or cellular uptake of siRNA. However, efforts to develop libraries have so far concentrated on hydrazone bridges to monocationic heads. Here, we report synthesis efforts to enlarge this focused library with oxime and disulfide bridges and dynamic amphiphiles with more than one positive charge. Evaluation in fluorogenic vesicles reveals best activation of DNA as ion transporters by dynamic amphiphiles with dendritic scaffolds, doubly charged heads and four tails. Moreover, oximes, contrary to hydrazones, remain active under acidic conditions. Linear elongation of dendritic head-groups seems to cause increasing detergent effects and should therefore be avoided.

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Section: Resultsmentioning

confidence: 59%

Synthesis of an Enlarged Library of Dynamic DNA Activators with Oxime, Disulfide and Hydrazone Bridges

Montenegro

Bang

Sakai

et al. 2012

Chemistry A European J

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“…In addition to functional and structural modifications, a recent publication on the effect of counter ions may as well contribute to the 'permeability tool box' enabling the design of cellular active peptides without compromising on activity or selectivity. [26] Polyion-counterion complexes are reported as a universal motif to generate and modulate function in biomembranes in the broadest sense. Examples include transport, biosensing, aptamer sensing as well as cellular uptake of DNA, RNA and CPPs.…”

Section: Discussionmentioning

confidence: 99%

Towards Intracellular Delivery of Peptides

Marzinzik¹,

Vorherr

2013

Chimia

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In view of our more comprehensive understanding with respect to intracellular pathways and their regulation, a vast number of interesting drug targets appear to be in a space that can be addressed neither by small molecules nor by biologics. Especially, interference with intracellular protein-protein interactions, if successful, seems to offer considerable opportunities to expand the application of peptides as therapeutics, in particular in the field of oncology. This review focuses on requirements for the development of peptide therapeutics aiming at intracellular targets. In addition, an outlook for developments in this field based on recent examples for peptides active in cellular assays, highlighting key requirement to assess permeability, is provided.

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“…Inspired by investigations of the Matile group[28] on the importance of polyion-counter-ion complexes for cell penetration5 and remembering the perfect fit between guanidinium groups and so-called oxy-anions (Figure 3,a) that had been used in organic synthesis and in supramolecular chemistry,[30 – 36] we had prepared the 1:4 salt 1a -4 Fos of octaarginine amide and fosmidomycin to test its in vitro activity against P. falciparum , and we were able to report in 2013 that growth of this parasite (which causes malaria) was much more strongly reduced by the salt than by fosmidomycin itself (Figure 3,b and c). [37]6…”

Section: Introductionmentioning

confidence: 99%

Cell Penetration, Herbicidal Activity, and in‐vivo‐Toxicity of Oligo‐Arginine Derivatives and of Novel Guanidinium‐Rich Compounds Derived from the Biopolymer Cyanophycin

Grogg

Hilvert

Ebert

et al. 2018

Helvetica Chimica Acta

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Oligo-arginines are thoroughly studied cell-penetrating peptides (CPPs, Figures 1 and 2). Previous in-vitro investigations with the octaarginine salt of the phosphonate fosmidomycin (herbicide and anti-malaria drug) have shown a 40-fold parasitaemia inhibition with P. falciparum, compared to fosmidomycin alone (Figure 3). We have now tested this salt, as well as the corresponding phosphinate salt of the herbicide glufosinate, for herbicidal activity with whole plants by spray application, hoping for increased activities, i.e. decreased doses. However, both salts showed low herbicidal activity, indicating poor foliar uptake (Table 1). Another pronounced difference between in-vitro and in-vivo activity was demonstrated with various cell-penetrating octaarginine salts of fosmidomycin: intravenous injection to mice caused exitus of the animals within minutes, even at doses as low as 1.4 μmol/kg (Table 2). The results show that use of CPPs for drug delivery, for instance to cancer cells and tissues, must be considered with due care. The biopolymer cyanophycin is a poly-aspartic acid containing argininylated side chains (Figure 4); its building block is the dipeptide H-βAsp-αArg-OH (H-Adp-OH). To test and compare the biological properties with those of octaarginines we synthesized Adp8-derivatives (Figure 5). Intravenouse injection of H-Adp8-NH2 into the tail vein of mice with doses as high as 45 μmol/kg causes no symptoms whatsoever (Table 3), but H-Adp8-NH2 is not cell penetrating (HEK293 and MCF-7 cells, Figure 6). On the other hand, the fluorescently labeled octamers FAM-(Adp(OMe))8-NH2 and FAM-(Adp(NMe2))8-NH2 with ester and amide groups in the side chains exhibit mediocre to high cell-wall permeability (Figure 6), and are toxic (Table 3). Possible reasons for this behavior are discussed (Figure 7) and corresponding NMR spectra are presented (Figure 8).

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Conceptually New Entries into Cells

Cited by 11 publications

References 11 publications

Synthesis of an Enlarged Library of Dynamic DNA Activators with Oxime, Disulfide and Hydrazone Bridges

Synthesis of an Enlarged Library of Dynamic DNA Activators with Oxime, Disulfide and Hydrazone Bridges

Towards Intracellular Delivery of Peptides

Cell Penetration, Herbicidal Activity, and in‐vivo‐Toxicity of Oligo‐Arginine Derivatives and of Novel Guanidinium‐Rich Compounds Derived from the Biopolymer Cyanophycin

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