Department of Chemistry , University of California , One Shields Avenue , Davis , California 95616 , United States.
Children's National Medical Center , 111 Michigan Ave , NW, Washington, DC 20012 , United States.
J Org Chem. 2018 Sep 21;83(18):10798-10804. doi: 10.1021/acs.joc.8b01519. Epub 2018 Aug 23.
Streptococcus pneumoniae sialidase SpNanB is an intramolecular trans-sialidase (IT-sialidase) and a virulence factor that is essential for streptococcal infection of the upper and lower respiratory tract. SpNanB catalyzes the formation of 2,7-anhydro- N-acetylneuraminic acid (2,7-anhydro-Neu5Ac), a potential prebiotic that can be used as the sole carbon source of a common human gut commensal anaerobic bacterium. We report here the development of an efficient one-pot multienzyme (OPME) system for synthesizing 2,7-anhydro-Neu5Ac and its derivatives. Based on a crystal structure analysis, an N-cyclohexyl derivative of 2,7-anhydro-neuraminic acid was designed, synthesized, and shown to be a selective inhibitor against SpNanB and another Streptococcus pneumoniae sialidase SpNanC. This study demonstrates a new strategy of synthesizing 2,7-anhydro-sialic acids in a gram scale and the potential application of their derivatives as selective sialidase inhibitors.
肺炎链球菌唾液酸酶 SpNanB 是一种分子内转唾液酸酶（IT-唾液酸酶）和一种毒力因子，对于链球菌在上呼吸道和下呼吸道的感染是必不可少的。SpNanB 催化 2,7-脱水-N-乙酰神经氨酸（2,7-anhydro-Neu5Ac）的形成，这是一种潜在的益生元，可以作为一种常见的人类肠道共生厌氧细菌的唯一碳源。我们在这里报告了一种用于合成 2,7-脱水-Neu5Ac 及其衍生物的高效一锅多酶（OPME）系统的开发。基于晶体结构分析，设计、合成了 2,7-脱水-神经氨酸的 N-环己基衍生物，并证明它是 SpNanB 和另一种肺炎链球菌唾液酸酶 SpNanC 的选择性抑制剂。本研究展示了在克级规模上合成 2,7-脱水唾液酸的新策略，以及它们的衍生物作为选择性唾液酸酶抑制剂的潜在应用。
