Design, synthesis, and biological evaluation of novel KRN7000 analogues using 5α-gem-difluorocarba-β-l-arabinopyranose

IF 2.4 3区化学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Carbohydrate Research Pub Date : 2025-03-08 DOI:10.1016/j.carres.2025.109457

Yuanfang Liu , Chuanfang Zhao , Jun Liu , Yuguo Du

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Abstract

Two novel KRN7000 analogues, where d-galactopyranosyl residue was replaced by 5α-gem-difluorocarba-β-l-arabinopyranose, were designed based on docking computation and energy decomposition analyses. The target compounds were synthesized employing the key steps of Ferrier's carbocyclic ring closure and gem-difluoride formation with d-galactose as starting material. The in vivo bioassay revealed that the designed glycolipids could stimulate iNKT cells to produce cytokines IFN-γ and IL-4. The introduced hydroxyl groups on glycolipid acyl chain provided extra CD1d substrate affinities, and thus favored to boost Th1-type cytokine secretion. When the ring oxygen was replaced by CF₂ group on sugar unit, its TCR affinities were enhanced in contrast with KRN7000. The in vivo cytokine profiles induced by synthetic glycolipids were initially dominated by the binding ability of CD1/glycolipid, and then adjusted by affinity toward TCR in CD1/α-GalCer/TCR triplex structure. The current results could be helpful in designing of more efficient α-GalCer analogs.

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使用5α-宝石-二氟化ba-β-l-阿拉伯吡喃糖的新型KRN7000类似物的设计、合成和生物学评价

基于对接计算和能量分解分析，设计了两种新型KRN7000类似物，其中d-半乳糖吡喃糖残基被5α-宝石-二氟化ba-β-l-阿拉伯吡喃糖取代。以d-半乳糖为原料，采用Ferrier碳环闭合和宝石二氟化形成的关键步骤合成了目标化合物。体内生物实验表明，所设计的糖脂能刺激iNKT细胞产生细胞因子IFN-γ和IL-4。糖脂酰基链上引入的羟基提供了额外的CD1d底物亲和力，从而有利于促进th1型细胞因子的分泌。当糖单元上的环氧被CF2基团取代时，其TCR亲和性比KRN7000增强。合成糖脂诱导的体内细胞因子分布最初受CD1/糖脂的结合能力支配，然后受CD1/α-GalCer/TCR三联体结构中对TCR的亲和力调节。本研究结果可为设计更高效的α-GalCer类似物提供参考。

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来源期刊

Carbohydrate Research 化学-生化与分子生物学

CiteScore

5.00

自引率

3.20%

发文量

183

审稿时长

3.6 weeks

期刊介绍： Carbohydrate Research publishes reports of original research in the following areas of carbohydrate science: action of enzymes, analytical chemistry, biochemistry (biosynthesis, degradation, structural and functional biochemistry, conformation, molecular recognition, enzyme mechanisms, carbohydrate-processing enzymes, including glycosidases and glycosyltransferases), chemical synthesis, isolation of natural products, physicochemical studies, reactions and their mechanisms, the study of structures and stereochemistry, and technological aspects. Papers on polysaccharides should have a "molecular" component; that is a paper on new or modified polysaccharides should include structural information and characterization in addition to the usual studies of rheological properties and the like. A paper on a new, naturally occurring polysaccharide should include structural information, defining monosaccharide components and linkage sequence. Papers devoted wholly or partly to X-ray crystallographic studies, or to computational aspects (molecular mechanics or molecular orbital calculations, simulations via molecular dynamics), will be considered if they meet certain criteria. For computational papers the requirements are that the methods used be specified in sufficient detail to permit replication of the results, and that the conclusions be shown to have relevance to experimental observations - the authors'' own data or data from the literature. Specific directions for the presentation of X-ray data are given below under Results and "discussion".