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Nonpyrogenic Molecular Adjuvants Based on norAbu-Muramyldipeptide and norAbu-Glucosaminyl Muramyldipeptide: Synthesis, Molecular Mechanisms of Action, and Biological Activities in Vitro and in Vivo
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-08 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00593
Roman Effenberg 1 , Pavlína Turánek Knötigová 2 , Daniel Zyka 3 , Hana Čelechovská 2 , Josef Mašek 2 , Eliška Bartheldyová 2 , František Hubatka 2 , Štěpán Koudelka 2 , Róbert Lukáč 2 , Anna Kovalová 4 , David Šaman 4 , Michal Křupka 5 , Lucia Barkocziova 5 , Petr Kosztyu 5 , Marek Šebela 6 , Ladislav Drož 3 , Michal Hučko 3, 7 , Mária Kanásová 3, 8 , Andrew D. Miller 2, 9, 10 , Milan Raška 2, 5 , Miroslav Ledvina 1 , Jaroslav Turánek 2
Affiliation  

Fatty acyl analogues of muramyldipeptide (MDP) (abbreviated N-L18 norAbuGMDP, N-B30 norAbuGMDP, norAbuMDP-Lys(L18), norAbuMDP-Lys(B30), norAbuGMDP-Lys(L18), norAbuGMDP-Lys(B30), B30 norAbuMDP, L18 norAbuMDP) are designed and synthesized comprising the normuramyl-l-α-aminobutanoyl (norAbu) structural moiety. All new analogues show depressed pyrogenicity in both free (micellar) state and in liposomal formulations when tested in rabbits in vivo (sc and iv application). New analogues are also shown to be selective activators of NOD2 and NLRP3 (inflammasome) in vitro but not NOD1. Potencies of NOD2 and NLRP3 stimulation are found comparable with free MDP and other positive controls. Analogues are also demonstrated to be effective in stimulating cellular proliferation when the sera from mice are injected sc with individual liposome-loaded analogues, causing proliferation of bone marrow-derived GM-progenitors cells. Importantly, vaccination nanoparticles prepared from metallochelation liposomes, His-tagged antigen rOspA from Borrelia burgdorferi, and lipophilic analogue norAbuMDP-Lys(B30) as adjuvant, are shown to provoke OspA-specific antibody responses with a strong Th1-bias (dominance of IgG2a response). In contrast, the adjuvant effects of Alum or parent MDP show a strong Th2-bias (dominance of IgG1 response).

中文翻译:

基于norAbu-Muramyldipeptide和norAbu-Glucosaminyl Muramyldipeptide的非热原性分子佐剂:合成,作用分子机制和体内和体外生物学活性

muramyldipeptide(MDP)的脂肪酰基类似物(缩写为N -L18 norAbuGMDP,N -B30 norAbuGMDP,norAbuMDP-Lys(L18),norAbuMDP-Lys(B30),norAbuGMDP-Lys(L18),norAbuGMDP-Lys(B30) ,L18 norAbuMDP)的设计和合成,其中包含normuramyl- 1-α-氨基丁酰基(norAbu)结构部分。在兔体内(sc和iv应用)进行测试时,所有新的类似物在游离(胶束)状态和脂质体制剂中均显示出降低的热原性。还显示出新的类似物在体外是NOD2和NLRP3(炎性体)的选择性活化剂,而不是NOD1。发现NOD2和NLRP3刺激的潜能与游离MDP和其他阳性对照相当。当将来自小鼠的血清用单独的脂质体负载的类似物注射皮下注射,引起骨髓来源的GM祖细胞的增殖时,类似物也被证明在刺激细胞增殖中是有效的。重要的是,由金属螯合脂质体,博氏疏螺旋体Borrelia burgdorferi)的His标记抗原rOspA制备的疫苗接种纳米颗粒,和亲脂性类似物norAbuMDP-Lys(B30)作为佐剂,显示出具有强烈的Th1-bias(IgG2a反应优势)的OspA特异性抗体反应。相反,明矾或母体MDP的佐剂作用显示出较强的Th2-bias(IgG1反应优势)。
更新日期:2017-09-08
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