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首页> 外文期刊>Chemistry: A European journal >Chemoenzymatic Synthesis of a Glycolipid Library and Elucidation of the Antigenic Epitope for Construction of a Vaccine Against Lyme Disease
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Chemoenzymatic Synthesis of a Glycolipid Library and Elucidation of the Antigenic Epitope for Construction of a Vaccine Against Lyme Disease

机译：糖脂库的化学酶法合成和抗原表位的阐明，用于构建针对莱姆病的疫苗

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摘要

Lyme disease (LD) is the most common tick-borne disease in Europe, North America, and Asia. The etiologic agents of LD are spirochetes of the group Borrelia burgdorferi sensu lato, which possess a lipid content of 25-30% of the dry weight. The major glycolipid cholesteryl 6-O-acyl-beta-D-galactopyranoside (ACGal), present in B. burgdorferi sensu stricto, B. afzelii, and B. garinii, is a specific and highly prevalent antigen frequently recognized by antibodies in late-stage LD. Here we report a convenient route for the chemical synthesis of ACGal by employing a combination of chemical synthesis steps with enzymatic transformations. This synthesized molecule was compared with bacterial extracts by immunoblots with patient sera, confirming the preserved antigenicity. Next, a glycolipid library derived from the native molecules with variations in the fatty acyl moiety and derivatives in which the cholesterol has been replaced was designed and synthesized. The chemical structures were confirmed by 1D and 2D NMR spectroscopy and mass spectrometry. The native and synthetic glycolipids were utilized in immunoblots to determine the epitope recognized by antibodies in patient sera. By this method we could demonstrate that galactose, cholesterol, and a fatty acid with a minimal chain length of four carbon atoms comprises the essential structure for recognition by antibodies. Finally, this finding allowed the synthesis of a functionalized ACGal with an omega-mercapto group at the fatty acid and a facile protection and deprotection strategy. This antigenic hapten can be conjugated to a carrier protein to effect immunization against Lyme disease.
机译：莱姆病（LD）是欧洲，北美和亚洲最常见的壁虱传播疾病。 LD的病原体是Borrelia burgdorferi sensu lato组的螺旋体，其脂质含量为干重的25-30％。存在于B. burgdorferi sensustricto，B。afzelii和B. garinii中的主要糖脂胆固醇基6-O-酰基-β-D-吡喃半乳糖苷（ACGal）是一种特异且高度流行的抗原，常被晚期抗体所识别。 LD阶段。在这里，我们报告了通过化学合成步骤与酶促转化相结合的化学合成ACGal的便捷途径。通过用患者血清进行免疫印迹将该合成的分子与细菌提取物进行比较，确认了保留的抗原性。接下来，设计并合成了衍生自具有脂肪酰基部分变化的天然分子的糖脂文库和其中胆固醇已被取代的衍生物。化学结构通过1D和2D NMR光谱法和质谱法确认。将天然和合成的糖脂用于免疫印迹，以确定患者血清中抗体识别的表位。通过这种方法，我们可以证明半乳糖，胆固醇和具有最小四个碳原子链长的脂肪酸构成了抗体识别的基本结构。最后，该发现允许合成在脂肪酸上具有ω-巯基的官能化ACGal，并具有简便的保护和脱保护策略。该抗原半抗原可以与载体蛋白缀合以实现针对莱姆病的免疫。

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