Synthesis and characterization of PEGylated toll like receptor 7 ligands.
Synthesis and characterization of PEGylated toll like receptor 7 ligands.
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DOI：
10.1021/bc1004813
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发表时间：
2011-03-16
影响因子：
4.7
通讯作者：
Carson, Dennis A.
中科院分区：
文献类型：
--
作者：
Chan, Michael;Hayashi, Tomoko;Mathewson, Richard D.;Yao, Shiyin;Gray, Christine;Tawatao, Rommel I.;Kalenian, Kevin;Zhang, Yanmei;Hayashi, Yuki;Lao, Fitzgerald S.;Cottam, Howard B.;Carson, Dennis A.
Toll样受体7（TLR 7）位于免疫细胞的内体区室中。由衔接蛋白MyD 88介导的通过TLR 7的信号传导刺激先天免疫系统并形成适应性免疫应答。以前，我们的特点是TLR 7配体共轭蛋白质，脂质或聚乙二醇（PEG）。在TLR 7配体缀合物中，PEG链的添加降低了激动效力。PEG对人体安全，广泛用于改善现有生物制剂和一些低分子量化合物的药代动力学。PEG修饰可能是改变TLR 7配体的药代动力学和药效学的可行方法。在这项研究中，我们系统地研究了PEG链长对有效的TLR 7配体的体外和体内性质的影响。PEG化增加了TLR 7配体的溶解度并调节了蛋白质结合。将6-10长度的PEG添加到TLR 7配体降低了其在体外通过鼠巨噬细胞诱导白细胞介素（IL）-6以及在体内诱导IL-6和肿瘤坏死因子（TNF）的效力。然而，具有18或更长链的PEG化恢复甚至增强了药物的激动活性。在人外周血单核细胞中，观察到PEG化对促炎性细胞因子IL-6、IL-12、TNF-α、IL-1β和1型干扰素的分泌以及对B细胞增殖的类似影响。总之，这些研究表明，PEG链与合成TLR配体的缀合可以影响其细胞因子诱导的效力，这取决于PEG部分的大小。因此，PEG化可能是调节TLR 7配体药理学性质的可行方法。
Toll like receptor 7 (TLR7) is located in the endosomal compartment of immune cells. Signaling through TLR7, mediated by the adaptor protein MyD88, stimulates the innate immune system and shapes adaptive immune responses. Previously, we characterized TLR7 ligands conjugated to protein, lipid or polyethylene glycol (PEG). Among the TLR7 ligand conjugates, the addition of PEG chains reduced the agonistic potency. PEGs are safe in humans and widely used for improvement of pharmacokinetics in existing biologics and some low molecular weight compounds. PEGylation could be a feasible method to alter the pharmacokinetics and pharmacodynamics of TLR7 ligands. In this study, we systematically studied the influence of PEG chain length on the in vitro and in vivo properties of potent TLR7 ligands. PEGylation increased solubility of the TLR7 ligands and modulated protein binding. Adding a 6–10 length PEG to the TLR7 ligand reduced its potency toward induction of interleukin (IL)-6 by murine macrophages in vitro and IL-6 and tumor necrosis factor (TNF) in vivo. However, PEGylation with 18 or longer chain restored, and even enhanced, the agonistic activity of the drug. In human peripheral blood mononuclear cells, similar effects of PEGylation were observed for secretion of proinflammatory cytokines, IL-6, IL-12, TNF-α, IL-1β and type 1 interferon, as well for B cell proliferation. In summary, these studies demonstrate that conjugation of PEG chains to a synthetic TLR ligand can impact its potency for cytokine induction depending on the size of the PEG moiety. Thus, PEGylation may be a feasible approach to regulate the pharmacological properties of TLR7 ligands.
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DOI：
10.1073/pnas.0631696100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Lee, J;Chuang, TH;Cottam, HB
通讯作者：
Cottam, HB
影响因子：
8.4
作者：
Grimm, Martin;Kim, Mia;Gasser, Martin
通讯作者：
Gasser, Martin
影响因子：
4.7
作者：
Chan M;Hayashi T;Kuy CS;Gray CS;Wu CC;Corr M;Wrasidlo W;Cottam HB;Carson DA
通讯作者：
Carson DA
影响因子：
10.8
作者：
Greenwald, RB
通讯作者：
Greenwald, RB
影响因子：
21.3
作者：
Lee, Jongdae;Mo, Ji-Hun;Raz, Eyal
通讯作者：
Raz, Eyal