Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists.
Synthesis of Conformationally Constrained d-Glu-meso-DAP Analogs as Innate Immune Agonists.
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DOI：
10.3390/molecules25225228
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发表时间：
2020-11-10
期刊：
影响因子：
--
通讯作者：
Jakopin Ž
中科院分区：
文献类型：
--
作者：
Guzelj S;Jakopin Ž
二肽d-Glu-meso-DAP（iE-DAP）是能够激活先天免疫受体核苷酸结合寡聚化结构域蛋白（NOD 1）的最小结构片段。已知内消旋-二氨基庚二酸（meso-DAP）部分在允许的结构修饰方面是非常严格的，所述结构修饰仍然保留NOD 1活性。我们研究的目的是进一步探索meso-DAP部分周围的化学空间，并提供对NOD 1激动所需的结构特征的更深入理解。为了实现meso-DAP端胺官能团的刚性化，在其侧链上引入异恶唑啉和吡啶杂环。此外，我们将所获得的meso-DAP模拟物并入iE-DAP的结构中。总的来说，九个创新的iE-DAP衍生物，另外配备了月桂酰基或双十二烷基部分的α-氨基的d-Glu已经制备和检查其NOD 1激活能力。总体而言，所获得的结果表明，限制内消旋-DAP的末端氨基消除了化合物活化NOD 1的能力，因为只有化合物6 b保留了值得注意的NOD 1激动活性，并且支持了该氨基酸在允许的结构修饰方面的严格性质。
The dipeptide d-Glu-meso-DAP (iE-DAP) is the minimal structural fragment capable of activating the innate immune receptor nucleotide-binding oligomerization domain protein (NOD1). The meso-diaminopimelic acid (meso-DAP) moiety is known to be very stringent in terms of the allowed structural modifications which still retain the NOD1 activity. The aim of our study was to further explore the chemical space around the meso-DAP portion and provide a deeper understanding of the structural features required for NOD1 agonism. In order to achieve the rigidization of the terminal amine functionality of meso-DAP, isoxazoline and pyridine heterocycles were introduced into its side-chain. Further, we incorporated the obtained meso-DAP mimetics into the structure of iE-DAP. Collectively, nine innovative iE-DAP derivatives additionally equipped with lauroyl or didodecyl moieties at the α-amino group of d-Glu have been prepared and examined for their NOD1 activating capacity. Overall, the results obtained indicate that constraining the terminal amino group of meso-DAP abrogates the compounds’ ability to activate NOD1, since only compound 6b retained noteworthy NOD1 agonistic activity, and underpin the stringent nature of this amino acid with regard to the allowed structural modifications.
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