Department of Biotechnology and Biosciences, University of Milano-Bicocca , Piazza della Scienza, 2, 20126 Milano, Italy.
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale, Università di Parma , Parco Area delle Scienze 17/a, 43124 Parma, Italy.
J Med Chem. 2017 Jun 22;60(12):4882-4892. doi: 10.1021/acs.jmedchem.7b00095. Epub 2017 May 15.
We recently reported on the activity of cationic amphiphiles in inhibiting TLR4 activation and subsequent production of inflammatory cytokines in cells and in animal models. Starting from the assumption that opportunely designed cationic amphiphiles can behave as CD14/MD-2 ligands and therefore modulate the TLR4 signaling, we present here a panel of amphiphilic guanidinocalixarenes whose structure was computationally optimized to dock into MD-2 and CD14 binding sites. Some of these calixarenes were active in inhibiting, in a dose-dependent way, the LPS-stimulated TLR4 activation and TLR4-dependent cytokine production in human and mouse cells. Moreover, guanidinocalixarenes also inhibited TLR4 signaling when TLR4 was activated by a non-LPS stimulus, the plant lectin PHA. While the activity of guanidinocalixarenes in inhibiting LPS toxic action has previously been related to their capacity to bind LPS, we suggest a direct antagonist effect of calixarenes on TLR4/MD-2 dimerization, pointing at the calixarene moiety as a potential scaffold for the development of new TLR4-directed therapeutics.
我们最近报道了阳离子两亲物在抑制 TLR4 激活及其在细胞和动物模型中随后产生炎症细胞因子方面的活性。基于阳离子两亲物可以作为 CD14/MD-2 配体发挥作用并因此调节 TLR4 信号的假设，我们在此提出了一组两亲性胍基杯芳烃，其结构经过计算优化以与 MD-2 和 CD14 结合位点对接。这些杯芳烃中的一些能够以剂量依赖的方式抑制 LPS 刺激的 TLR4 激活和人源和鼠源细胞中 TLR4 依赖性细胞因子的产生。此外，当 TLR4 被植物凝集素 PHA 非 LPS 刺激激活时，胍基杯芳烃也抑制 TLR4 信号。虽然胍基杯芳烃抑制 LPS 毒性作用的活性以前与它们结合 LPS 的能力有关，但我们提出杯芳烃对 TLR4/MD-2 二聚化具有直接的拮抗作用，指出杯芳烃部分是开发新的 TLR4 导向治疗剂的潜在支架。
