Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity.
Synthetic Glycolipids as Molecular Vaccine Adjuvants: Mechanism of Action in Human Cells and In Vivo Activity.
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DOI：
10.1021/acs.jmedchem.1c00896
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发表时间：
2021-08-26
影响因子：
7.3
通讯作者：
Peri F
中科院分区：
文献类型：
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作者：
Facchini FA;Minotti A;Luraghi A;Romerio A;Gotri N;Matamoros-Recio A;Iannucci A;Palmer C;Wang G;Ingram R;Martin-Santamaria S;Pirianov G;De Andrea M;Valvano MA;Peri F
用于疫苗制剂的现代佐剂是免疫刺激剂，其作用基于通过定义明确的配体激活模式识别受体（PRRs），以增强先天和适应性免疫反应。单磷酰脂质A （MPLA）是一种解毒的脂质A类似物，是一种临床批准的刺激toll样受体4 （TLR4）的佐剂。MPLA的合成对制造和质量评价提出了挑战。为了弥补这一差距，我们在这里报告了化学简化的TLR4激动剂的开发和临床前测试，这种激动剂可以持续地以高纯度和大规模生产。在计算和生物实验的基础上，我们发现合成的单糖分子（FP化合物）以亚微摩尔的亲和力与TLR4/MD-2二聚体结合，稳定了活性受体的构象。这导致MyD88和trif依赖的TLR4信号和NLRP3炎性体的激活。FP化合物缺乏体内毒性，并通过刺激抗体反应表现出佐剂活性，其效力与MPLA相当。
Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA.
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影响因子：
4.4
作者：
Li, Hanfen;Willingham, Stephen B.;Ting, Jenny P. -Y.;Re, Fabio
通讯作者：
Re, Fabio
影响因子：
29.7
作者：
Brubaker SW;Bonham KS;Zanoni I;Kagan JC
通讯作者：
Kagan JC
影响因子：
56.9
作者：
Mata-Haro, Veronica;Cekic, Caglar;Mitchell, Thomas C.
通讯作者：
Mitchell, Thomas C.
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
DOI：
10.1007/978-1-62703-523-1_9
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Jakobs, Christopher;Bartok, Eva;Hornung, Veit
通讯作者：
Hornung, Veit