Effect of Terminal-Group Functionality on the Ability of Dendrimers to Bind Proteins

Chiba, Fumiko; Twyman, Lance J.

doi:10.1021/acs.bioconjchem.7b00350

Cited by 6 publications

(11 citation statements)

References 27 publications

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“…This is particularly relevant for α-chymotrypsin whose active site entrance is rich in positive charge . We have previously exploited this principle when demonstrating a size based relationship between dendrimers and protein binding. , De and Dravid used the same premise to demonstrate how unfunctionalized GO, which is rich in negative charge, could interact electrostatically with α-chymotrypsin . However, electrostatics are not the only interactions involved in protein binding.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, changes in binding strength occur when functionalized macromolecules are used as protein ligands. These include functionalized porphyrins, linear polymers, and dendrimers …”

Section: Introductionmentioning

confidence: 99%

“…These include functionalized porphyrins, 15 linear polymers, 16 and dendrimers. 17 The aim of the work described within this paper was to determine whether or not the already significant protein binding ability of GO could be improved through functionalization. Of particular interest is functionalization with amino acids.…”

Section: ■ Introductionmentioning

confidence: 99%

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Synthesis of Oligomeric and Monomeric Functionalized Graphene Oxides and a Comparison of Their Abilities to Perform as Protein Ligands and Enzyme Inhibitors

Aziz

Twyman

2019

ACS Appl. Mater. Interfaces

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Graphene oxide (GO) is a versatile, monomolecular layered nanomaterial that possesses various oxygen-containing functionality on its large surface. These characteristics allow GO to interact with a variety of materials and to be applied towards a number of areas. The strength and selectivity of these interactions can be improved significantly through further functionalization. In this paper, we describe the functionalization of GO and its application as a protein ligand and an enzyme inhibitor. The work reported in this paper details how chymotrypsin inhibition can be improved using GO functionalized with a monomeric and oligomer layer of tyrosine. The results indicated that the mono- and oligo-functionalized systems performed extremely well, with K i values nearly four times better than GO alone. Our original premise was that the oligomeric system would bind better because of the length of the oligomeric arms and potential for a high degree of flexibility. However, the results clearly showed that the shorter monomeric system was the better ligand/inhibitor. This was due to weaker intramolecular interactions between the aromatic side chains of tyrosine and the aromatic surface of GO. Although these are possible for both systems, they are cooperative and therefore stronger for the oligomeric functionalized GO. As such, the protein must compete and overcome these cooperative intramolecular interactions before it can bind to the functionalized GO, whereas the tyrosines on the surface of the monomeric system interact with the surface of GO through a significantly weaker monovalent interaction, but interact cooperatively with the protein surface.

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Section: Resultsmentioning

confidence: 99%

“…Therefore, changes in binding strength occur when functionalized macromolecules are used as protein ligands. These include functionalized porphyrins, linear polymers, and dendrimers …”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Oligomeric and Monomeric Functionalized Graphene Oxides and a Comparison of Their Abilities to Perform as Protein Ligands and Enzyme Inhibitors

Aziz

Twyman

2019

ACS Appl. Mater. Interfaces

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“…Dendrimer branches can act as selective gates to control the entry of small molecules [ 100 ]. Terminal groups on the dendrimer boundary can be adjusted to manage the solubility [ 101 ] and used as anchor points to enable functionalization with drugs, antibodies and polymers [ 102 , 103 ].…”

Section: Nanotechnologies In Pancreatic Cancermentioning

confidence: 99%

Nanotechnologies in Pancreatic Cancer Therapy

et al. 2017

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Pancreatic cancer has been classified as a cancer of unmet need. After diagnosis the patient prognosis is dismal with few surviving over 5 years. Treatment regimes are highly patient variable and often the patients are too sick to undergo surgical resection or chemotherapy. These chemotherapies are not effective often because patients are diagnosed at late stages and tumour metastasis has occurred. Nanotechnology can be used in order to formulate potent anticancer agents to improve their physicochemical properties such as poor aqueous solubility or prolong circulation times after administration resulting in improved efficacy. Studies have reported the use of nanotechnologies to improve the efficacy of gemcitabine (the current first line treatment) as well as investigating the potential of using other drug molecules which have previously shown promise but were unable to be utilised due to the inability to administer through appropriate routes—often related to solubility. Of the nanotechnologies reported, many can offer site specific targeting to the site of action as well as a plethora of other multifunctional properties such as image guidance and controlled release. This review focuses on the use of the major nanotechnologies both under pre-clinical development and those which have recently been approved for use in pancreatic cancer therapy.

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“…In particular, HPG-based dendrimers have the advantage of the polyether backbone with hydroxyl end groups that afford high biocompatibility . Moreover, HPG is an ideal platform to design conjugated biomaterials using numerous functionalizable surface hydroxyl groups. , HPG is functionalized with three different antiamyloidogenic small molecules such as gallic acid, , trehalose, and tyrosine . Gallic acid is the building block of most of the natural polyphenols, and trehalose is a disaccharide, and both are shown to have an antiamyloidogenic activity .…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule-Functionalized Hyperbranched Polyglycerol Dendrimers for Inhibiting Protein Aggregation

et al. 2020

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Amyloid protein aggregation is responsible for a variety of neurodegenerative diseases, and antiamyloidogenic small molecules are identified for inhibiting such protein aggregation at extra-/intracellular space. We show that the nanoparticle form of small molecules offers better antiamyloidogenic performance via enhanced bioavailability and multivalent binding with protein. Here, we report hyperbranched polyglycerol dendrimers terminated with antiamyloidogenic small molecules such as gallate, tyrosine, and trehalose and their potential in inhibiting lysozyme/huntingtin protein aggregation under intra-/extracellular space. The synthesized functional dendrimers are ∼5 nm in size having an average molecular weight of ∼2000 Da, and they are highly biocompatible in nature. We found that functional dendrimers are efficient in micromolar doses with respect to molecular forms that are effective at millimolar concentration. It is observed that the trehalose-terminated dendrimer is more effective in inhibiting protein aggregation, whereas the gallate-terminated dendrimer is more effective in disintegrating mature protein fibrils. This approach can be used to design functional dendrimers as potential nanodrugs for the treatment of various neurodegenerative diseases.

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Effect of Terminal-Group Functionality on the Ability of Dendrimers to Bind Proteins

Cited by 6 publications

References 27 publications

Synthesis of Oligomeric and Monomeric Functionalized Graphene Oxides and a Comparison of Their Abilities to Perform as Protein Ligands and Enzyme Inhibitors

Synthesis of Oligomeric and Monomeric Functionalized Graphene Oxides and a Comparison of Their Abilities to Perform as Protein Ligands and Enzyme Inhibitors

Nanotechnologies in Pancreatic Cancer Therapy

Small-Molecule-Functionalized Hyperbranched Polyglycerol Dendrimers for Inhibiting Protein Aggregation

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