Stable Deuterium Labeling of Histidine-Rich Lysine-Based Dendrimers

Sheveleva, Nadezhda N.; Markelov, Denis A.; Vovk, Mikhail A.; Tarasenko, I. I.; Mikhailova, M. E.; Ilyash, Maxim Y.; Neelov, Igor M.; Lähderanta, E.

doi:10.3390/molecules24132481

Cited by 19 publications

(20 citation statements)

References 41 publications

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“…Computer simulation of peptide dendrimers was performed earlier by Brownian dynamics [59], molecular dynamics [60,61] methods, and by a numerical self-consistent field approach [62]. Synthesis and NMR study of some new peptide dendrimers with internally inserted amino acid spacers between each pair of branching points were also described in recent papers [63][64][65][66].…”

Section: Introductionmentioning

confidence: 99%

Comparison of Structure and Local Dynamics of Two Peptide Dendrimers with the Same Backbone but with Different Side Groups in Their Spacers

et al. 2020

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In this paper, we perform computer simulation of two lysine-based dendrimers with Lys-2Lys and Lys-2Gly repeating units. These dendrimers were recently studied experimentally by NMR (Sci. Reports, 2018, 8, 8916) and tested as carriers for gene delivery (Bioorg. Chem., 2020, 95, 103504). Simulation was performed by molecular dynamics method in a wide range of temperatures. We have shown that the Lys-2Lys dendrimer has a larger size but smaller fluctuations as well as lower internal density in comparison with the Lys-2Gly dendrimer. The Lys-2Lys dendrimer has larger charge but counterions form more ion pairs with its NH 3 + groups and reduce the bare charge and zeta potential of the first dendrimer more strongly. It was demonstrated that these differences between dendrimers are due to the lower flexibility and the larger charge (+2) of each 2Lys spacers in comparison with 2Gly ones. The terminal CH 2 groups in both dendrimers move faster than the inner CH 2 groups. The calculated temperature dependencies of the spin-lattice relaxation times of these groups for both dendrimers are in a good agreement with the experimental results obtained by NMR.

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Section: Introductionmentioning

confidence: 99%

Comparison of Structure and Local Dynamics of Two Peptide Dendrimers with the Same Backbone but with Different Side Groups in Their Spacers

et al. 2020

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“…Recently new lysine-based peptide dendrimers with repeating units Lys-2Lys, Lys-2Gly, Lys-2Arg, Lys-2His, which consist of lysine branching points and dipeptide spacers (2Lys, 2Gly, 2Arg, 2His) between them have been synthesized and studied by NMR [ 52 , 53 , 54 ]. The unexpected slowing down of the orientational mobility of the side CH

groups in 2Arg spacers [ 53 ] was found.…”

Section: Introductionmentioning

confidence: 99%

Why the Orientational Mobility in Arginine and Lysine Spacers of Peptide Dendrimers Designed for Gene Delivery Is Different?

Bezrodnyi

Shavykin

Mikhtaniuk

et al. 2020

IJMS

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New peptide dendrimer with Lys-2Arg repeating units was recently studied experimentally by NMR (RSC Advances, 2019, 9, 18018) and tested as gene carrier successfully (Int. J. Mol. Sci., 2020, 21, 3138). The unusual slowing down of the orientational mobility of 2Arg spacers in this dendrimer was revealed. It has been suggested that this unexpected behavior is caused by the Arg-Arg pairing effect in water, which leads to entanglements between dendrimer branches. In this paper, we determine the reason for this slowing down using atomistic molecular dynamics simulation of this dendrimer. We present that the structural properties of Lys-2Arg dendrimer are close to those of the Lys-2Lys dendrimer at all temperatures (Polymers, 2020, 12, 1657). However, the orientational mobility of the H-H vector in CH2-N groups of 2Arg spacers in Lys-2Arg dendrimer is significantly slower than the mobility of the same vector in the Lys-2Lys dendrimer. This result is in agreement with the recent NMR experiments for the same systems. We revealed that this difference is not due to the arginine-arginine pairing, but is due to the semiflexibility effect associated with the different contour length from CH2-N group to the end of the side arginine or lysine segment in spacers.

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“…In light of these results, it seemed reasonable to continue the research on the use of PLL dendrimers as carriers for other types of genetic material. Substitution of lysine residues with different amino acids may bring several benefits to PLL dendrimers considered as a system for gene delivery, changing their flexibility and distribution of charged groups, providing additional interactions with nucleic acids, and affecting cellular uptake levels [24,[33][34][35]. Both lysine and arginine are charged aliphatic amino acids with amino groups that are protonated under biological conditions, which may ensure the efficient delivery of nucleic acid into the cells and its endosomal escape.…”

Section: Resultsmentioning

confidence: 99%

“…PLL dendrimers of the 3rd generation (D3): D3K2 (containing two additional lysine residues (Lys-Lys) between each pair of neighboring branching points of standard lysine dendrimer of the 3rd generation), D3R2 and D3H2 (with two additional arginine (Arg-Arg), or histidine (His-His) residues, respectively, between the same branching points) ( Figure 1) were synthesized, purified, and characterized as described previously [33][34][35].…”

Section: Dendrimersmentioning

confidence: 99%

Poly(lysine) Dendrimers Form Complexes with siRNA and Provide Its Efficient Uptake by Myeloid Cells: Model Studies for Therapeutic Nucleic Acid Delivery

Gorzkiewicz

Kopeć

Janaszewska

et al. 2020

IJMS

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The disruption of the cellular pathways of protein biosynthesis through the mechanism of RNA interference has been recognized as a tool of great diagnostic and therapeutic significance. However, in order to fully exploit the potential of this phenomenon, efficient and safe carriers capable of overcoming extra- and intracellular barriers and delivering siRNA to the target cells are needed. Recently, attention has focused on the possibility of the application of multifunctional nanoparticles, dendrimers, as potential delivery devices for siRNA. The aim of the present work was to evaluate the formation of dendriplexes using novel poly(lysine) dendrimers (containing lysine and arginine or histidine residues in their structure), and to verify the hypothesis that the use of these polymers may allow an efficient method of siRNA transfer into the cells in vitro to be obtained. The fluorescence polarization studies, as well as zeta potential and hydrodynamic diameter measurements were used to characterize the dendrimer:siRNA complexes. The cytotoxicity of dendrimers and dendriplexes was evaluated with the resazurin-based assay. Using the flow cytometry technique, the efficiency of siRNA transport to the myeloid cells was determined. This approach allowed us to determine the properties and optimal molar ratios of dendrimer:siRNA complexes, as well as to demonstrate that poly(lysine) dendrimers may serve as efficient carriers of genetic material, being much more effective than the commercially available transfection agent Lipofectamine 2000. This outcome provides the basis for further research on the application of poly(lysine) dendrimers as carriers for nucleic acids in the field of gene therapy.

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Stable Deuterium Labeling of Histidine-Rich Lysine-Based Dendrimers

Cited by 19 publications

References 41 publications

Comparison of Structure and Local Dynamics of Two Peptide Dendrimers with the Same Backbone but with Different Side Groups in Their Spacers

Comparison of Structure and Local Dynamics of Two Peptide Dendrimers with the Same Backbone but with Different Side Groups in Their Spacers

Why the Orientational Mobility in Arginine and Lysine Spacers of Peptide Dendrimers Designed for Gene Delivery Is Different?

Poly(lysine) Dendrimers Form Complexes with siRNA and Provide Its Efficient Uptake by Myeloid Cells: Model Studies for Therapeutic Nucleic Acid Delivery

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