Departments of Medicine, Infectious Diseases & Immunity, Imperial College London at Hammersmith Hospital, Ducane Road, London W12 ONN, UK.
Biomaterials. 2011 Nov;32(33):8702-11. doi: 10.1016/j.biomaterials.2011.07.085. Epub 2011 Aug 23.
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 modelling 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.
细菌脂多糖 (LPS)、Toll 样受体 4 (TLR4) 和 MD-2 之间的细胞表面相互作用是细菌性败血症综合征和伤口愈合的核心。我们已经表明，一种部分用氨基葡萄糖糖基化的第三代聚酰胺-胺 (PAMAM) 树枝状大分子通过抑制 TLR4-MD-2-LPS 诱导的炎症反应在兔组织瘢痕模型中发挥作用。然而，由于起始 PAMAM 树枝状大分子的多分散性，它是化学物质的密切相关混合物。具有单一化学物质状态的第二代三嗪树枝状大分子以低成本和千克级规模获得。PAMAM 树枝状大分子可以通过合成接枝到这个三嗪核树枝状大分子上，形成新的三嗪-PAMAM 杂化树枝状大分子。这使我们研究了是否可以使用分子建模方法来确定具有生物活性的先导分子的关键结构设计原则，该分子可以进行合成和生物学评估。我们描述了我们对几种基于树枝状大分子的构建体的计算机辅助分子研究以及确定的关键设计原则。我们的方法应该更广泛地适用于其他 TLR 受体的有针对性、合理和加速的分子设计。它们可用于治疗感染、炎症和恶性疾病。
