On Guanidinium and Cellular Uptake

Wexselblatt, Ezequiel; Esko, Jeffrey D.; Tor, Yitzhak

doi:10.1021/jo501101s

Cited by 77 publications

(78 citation statements)

References 82 publications

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“…[ 1 ] The same principle has been widely applied to enhance the internalization of cell‐penetrating peptides (CPPs), for example, by the incorporation of hydrophobic residues such as phenylalanine or tyrosine. [ 2,3 ] Ever since the first report of gene therapy by Merril et al in 1971, one of the pressing challenges we still face is the invention of an efficient non‐viral delivery vector that can transport genetic materials inside living cells. [ 4 ] The design of such synthetic vectors is often inspired by nature and it is frequently based on cationic macromolecules with well‐defined molecular weight, dispersity, and functionality.…”

Section: Polymer Samples Experimental [Mol%] Mnexperimental [G Mol–1]mentioning

confidence: 99%

Incorporation of Indole Significantly Improves the Transfection Efficiency of Guanidinium‐Containing Poly(Methacrylamide)s

Cokca

Zartner

Tabujew

et al. 2020

Macromol. Rapid Commun.

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A highly efficient transfection agent is reported that is based on terpolymer consisting of N‐(2‐hydroxypropyl)methacrylamide (HPMA), N‐(3‐guanidinopropyl) methacrylamide (GPMA), and N‐(2‐indolethyl)methacrylamide monomers (IEMA) by analogy to the amphipathic cell‐penetrating peptides containing tryptophan and arginine residues. The incorporation of the indole‐bearing monomer leads to successful plasmid DNA condensation even at a nitrogen‐to‐phosphate (N/P) ratio of 1. The hydrodynamic diameter of polyplexes is determined to be below 200 nm for all N/P ratios. The transfection studies demonstrate a 200‐fold increase of the transgene expression in comparison to P(HPMA‐co‐GPMA) with the same guanidinium content. This study reveals the strong potential of the indole group as a side‐chain pendant group that can increase the cellular uptake of polymers and the transfection efficiency of the respective polyplexes.

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Section: Polymer Samples Experimental [Mol%] Mnexperimental [G Mol–1]mentioning

confidence: 99%

Incorporation of Indole Significantly Improves the Transfection Efficiency of Guanidinium‐Containing Poly(Methacrylamide)s

Cokca

Zartner

Tabujew

et al. 2020

Macromol. Rapid Commun.

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“…Although other guanidinium-rich transporters [18][19][20][21][22][23] have been used to improve the intracellular delivery of liposomes, [24][25][26][27][28][29][30][31] GNeo is unique in being a highly lysosomotropic transporter capable of delivery through heparan sulfate exclusive pathways. 15 In addition to the universal benefits of liposomal packaging, incorporation of GNeo significantly increases the uptake and lysosomal delivery of diverse cargo compared to unmodified liposomes.…”

Section: -17mentioning

confidence: 99%

Delivery of an active lysosomal enzyme using GNeosomes

et al. 2016

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“…Another major reason to include guanidinium into a drug might be its potential role in facilitating cellular uptake. 58 Therefore, the guanidine derivatives have great potential to be promising novel drugs. Phe and Trp as well as Leu, Lys and Met tend to occur within 10 Å of Arg-Arg pairings.…”

Section: Acs Paragon Plus Environmentmentioning

confidence: 99%

Like-Charge Guanidinium Pairing between Ligand and Receptor: An Unusual Interaction for Drug Discovery and Design?

Yang

Zhang

et al. 2015

J. Phys. Chem. B

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A database survey in this study revealed for the first time that there are 227 counterintuitive like-charge guanidinium pairings (Gdm(+)-Arg pairings) between ligands and receptors in the Protein Data Bank, implying the potential guanidinium-arginine binding between guanidine-containing drugs and their target proteins. Furthermore, there are 145 guanidine-containing molecules in the DrugBank, showing the prevalence of guanidinium groups in drugs. It has also been reported that the introduction of a guanidinium group forming Gdm(+)-Arg pairing improved the potency of the drug by more than 8-fold in a typical case. On the basis of the survey, six ligand-protein complexes with typical Gdm(+)-Arg pairings were chosen for QM/MM calculations. The calculations at the B97-D/6-311++g(d,p) level revealed that the interaction could be as strong as -1.0 to -2.5 kcal/mol in DMSO and water, comparable to common intermolecular interactions. The calculations also unveiled that the Gdm(+)-Arg pairing interactions change from repulsive to attractive with the increase of dielectric constant, suggesting that the dielectric constant has a general stabilization effect on the Gdm(+)-Arg pairing. This study suggested that the like-charge guanidinium pairing interaction could be used not only for tuning the physical and chemical properties of drug leads but also for improving ligand binding affinity.

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On Guanidinium and Cellular Uptake

Cited by 77 publications

References 82 publications

Incorporation of Indole Significantly Improves the Transfection Efficiency of Guanidinium‐Containing Poly(Methacrylamide)s

Incorporation of Indole Significantly Improves the Transfection Efficiency of Guanidinium‐Containing Poly(Methacrylamide)s

Delivery of an active lysosomal enzyme using GNeosomes

Like-Charge Guanidinium Pairing between Ligand and Receptor: An Unusual Interaction for Drug Discovery and Design?

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