Synthesis of antifungal vaccines by conjugation of β-1,2 trimannosides with T-cell peptides and covalent anchoring of neoglycopeptide to tetanus toxoid
Synthesis of antifungal vaccines by conjugation of β-1,2 trimannosides with T-cell peptides and covalent anchoring of neoglycopeptide to tetanus toxoid
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DOI：
10.1016/j.carres.2014.06.024
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发表时间：
2015-02-11
影响因子：
3.1
通讯作者：
Bundle, David R.
中科院分区：
文献类型：
--
作者：
Cartmell, Jonathan;Paszkiewicz, Eugenia;Bundle, David R.
描述了构建新型三组分糖复合物疫苗的选择性策略，该疫苗在破伤风类毒素载体上呈递白色念珠菌细胞壁聚糖（β-1,2 甘露糖苷）和多肽片段。两种缀合策略中的第一种采用带有 N 末端硫代丙酰基残基的肽，用于与配备有丙烯酸酯接头的三糖缀合，以及 C 末端 S-乙酰基硫代乙醇基部分，用于随后将新糖肽与溴乙酰化破伤风类毒素连接。在弱碱性条件下，迈克尔将丙烯酸三糖加成到肽硫醇上，得到 N 端和 C 端糖肽硫醚的混合物。该策略的改进将 S-酰基保护与预期的硫酯交换平衡相协调。这提供了一种化学成分明确的全合成新糖肽缀合物，可以锚定到破伤风类毒素载体上，并避免引入外源抗原基团。第二种策略保留了N端硫代丙酰基残基，但用叠氮基取代了C端S-乙酸酯官能团，允许有效、选择性地形成新糖肽硫醚，并随后将其与炔丙化破伤风类毒素缀合，但引入了潜在的抗原性三唑键。 (C) 2014 Elsevier Ltd. 保留所有权利。
Selective strategies for the construction of novel three component glycoconjugate vaccines presenting Candida albicans cell wall glycan (beta-1,2 mannoside) and polypeptide fragments on a tetanus toxoid carrier are described. The first of two conjugation strategies employed peptides bearing an N-terminal thiopropionyl residue for conjugation to a trisaccharide equipped with an acrylate linker and a C- terminal S-acetyl thioglycolyl moiety for subsequent linking of neoglycopeptide to bromoacetylated tetanus toxoid. Michael addition of acrylate trisaccharides to peptide thiol under mildly basic conditions gave a mixture of N- and C-terminal glyco-peptide thioethers. An adaptation of this strategy coordinated S-acyl protection with anticipated thioester exchange equilibria. This furnished a single chemically defined fully synthetic neoglycopeptide conjugate that could be anchored to a tetanus toxoid carrier and avoids the introduction of exogenous antigenic groups. The second strategy retained the N-terminal thiopropionyl residue but replaced the C-terminal S-acetate functionality with an azido group that allowed efficient, selective formation of neoglycopeptide thioethers and subsequent conjugation of these with propargylated tetanus toxoid, but introduced potentially antigenic triazole linkages. (C) 2014 Elsevier Ltd. All rights reserved.