Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex

Abstract

The cell surface interaction between bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) and MD-2 is central to bacterial sepsis syndromes and wound healing. We have shown that a generation (G) 3.5 polyamidoamine (PAMAM) dendrimer that was partially glycosylated with glucosamine inhibits TLR4-MD-2-LPS induced inflammation in a rabbit model of tissue scaring. However, it was a mixture of closely related chemical species because of the polydispersity of the starting PAMAM dendrimer. Generation 2 triazine dendrimers with single chemical entity material status are available at low cost and at the kilogram scale. PAMAM dendrimer can be synthetically grafted onto this triazine core dendrimer to make new triazine-PAMAM hybrid dendrimers. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule that could be synthesized and biologically evaluated. We describe our computer aided molecular studies of several dendrimer based constructs and the key design principles identified. Our approach should be more broadly applicable to the biologically focused, rational and accelerated design of molecules for other TLR receptors. They could be useful for treating infectious, inflammatory and malignant diseases.

G5G2.5 core‐shell tecto‐dendrimer specifically targets reactive glia in brain ischemia

“…In this respect, G5G2.5 tecto-dendrimer shows a similar ability to that observed for G4-OH dendrimer in several recent reports (Dai et al 2010;Kannan et al 2012;Zhang et al 2016). In general terms, the cell specificity observed for different dendrimers seems to depend on the surface chemistry and the contextual inflammatory environment (Albertazzi et al 2010;Kim et al 2010;Barata et al 2011;Lesniak et al 2013;Zhang et al 2016); in line with this, in our experiments the G5G2.5 tectodendrimer showed increased uptake in ischemia-related neuroinflammation. Interestingly, astroglial uptake of the dendrimer is also increased in OGD conditions in vitro, even when astrocytes were devoid of other cell types.…”

Perspective: Dendrimer drugs for infection and inflammation

“…The power of this approach is considerable in providing important insights into parameters such as dendrimer size, shape, architecture, surface chemistry, and rigidity and flexibility. It enables the computer aided design of dendrimer drugs that can replicate the flexibility, cluster density, surface electrostatic charge and hydrophilicity of a synthetic ligand for a receptor [59]. The outcome is a much better basis on which to understand and predict the interaction of a dendrimer drug with a receptor.…”

Nanoparticles in wound healing from hope to promise from promise to routine

“…NO release decreases suppurative inflammation (131) and collagen degradation, minimises the bacterial burden (145), and inhibits fibroblasts to a lesser extent than clinically administered concentrations of antiseptics like povidone iodine (144). NO nanoparticles significantly accelerate wound healing (146) through modification of leukocyte migration and increasing tumour growth factor-β production with a subsequent promotion of angiogenesis (122,139), leading to increased fibroblast migration and collagen deposition (131,146). In infected wounds, stained NO nanoparticle-treated tissue depicts decreased neutrophil infiltrate and bacterial load, as well as rapid healing (145,(147)(148).…”