Structural studies of biologically active glycosylated polyamidoamine (PAMAM) dendrimers

Barata, Teresa; Shaunak, Sunil; Teo, Ian; Zloh, Mire; Brocchini, Steve

doi:10.1007/s00894-010-0907-1

Cited by 23 publications

(23 citation statements)

References 18 publications

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“…We found that the overall negative charge of the unmodified dendrimer's surface [7], [8] did not favour interactions with the negatively charged surface residues Glu92, Asp99 and Asp101 that line MD-2's hydrophobic pocket. This is the most likely explanation for the lack of biological activity of the unmodified dendrimer.…”

Section: Resultsmentioning

confidence: 81%

“…Our previous modelling studies suggested that a dendritic architecture was important for this molecule's biological activity [7], [8]. In addition, our previous biological studies [6] were preceded by unpublished observations with smaller generations of partially glycosylated PAMAM dendrimers; these molecules did not have the desired biological activity.…”

Section: Resultsmentioning

confidence: 94%

“…In the absence of information about the dendrimer's bioactive conformation, we had to use different conformations of the dendrimers for these rigid docking studies. We had already shown that the partially glycosylated dendrimer was very flexible by molecular dynamics simulations of fully solvated dendrimers [7], [8]. Initial 3D structures for the simulation were generated using our “sequence to conformation” method [7], [8].…”

Section: Resultsmentioning

confidence: 99%

“…We had already shown that the partially glycosylated dendrimer was very flexible by molecular dynamics simulations of fully solvated dendrimers [7], [8]. Initial 3D structures for the simulation were generated using our “sequence to conformation” method [7], [8]. Twenty representative conformations were then selected from these molecular dynamics trajectories.…”

Section: Resultsmentioning

confidence: 99%

“…Molecular modeling studies suggested, and experimental studies confirmed, that the surface loading of a G3.5 PAMAM dendrimer (with an average of 64 peripheral carboxylic acid groups) could not be increased beyond an absolute maximum cluster density of 12 evenly spaced surface glucosamine molecules using the divergent synthesis approach [7]. Frontier molecular orbital theory (FMOT) and molecular dynamics simulations also showed that the optimum surface loading and distribution of the zero length amide bond conjugated glucosamine molecules was determined by both electronic effects and the different dynamic conformations adopted by the modified dendrimer during the incremental addition of glucosamine [7], [8]. Importantly, the structural features and the dynamic behavior of this partially glycosylated dendrimer showed that its flexibility and polarity changed with the incremental addition of glucosamine molecules.…”

Section: Introductionmentioning

confidence: 98%

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Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

et al. 2011

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The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4′phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design additional macromolecular dendrimer based antagonists for other Toll Like Receptors. They could be useful for treating a spectrum of infectious, inflammatory and malignant diseases.

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Section: Resultsmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

et al. 2011

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Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

Teo

Toms²,

Marteyn

et al. 2012

EMBO Mol Med

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Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in β-defensin, IL-10, interferon-β, transforming growth factor-β, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.–>See accompanying article http://dx.doi.org/10.1002/emmm.201201668

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PAMAM Dendrimers: Destined for Success or Doomed to Fail? Plain and Modified PAMAM Dendrimers in the Context of Biomedical Applications

Łabieniec-Watała

Watała

2015

Journal of Pharmaceutical Sciences

123

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Structural studies of biologically active glycosylated polyamidoamine (PAMAM) dendrimers

Cited by 23 publications

References 18 publications

Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers

PAMAM Dendrimers: Destined for Success or Doomed to Fail? Plain and Modified PAMAM Dendrimers in the Context of Biomedical Applications

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