Ziaco Marcello, Górska Sabina, Traboni Serena, Razim Agnieszka, Casillo Angela, Iadonisi Alfonso, Gamian Andrzej, Corsaro Maria Michela, Bedini Emiliano
Department of Chemical Sciences, University of Naples Federico II, Complesso Universitario Monte S. Angelo , via Cintia 4, I-80126 Napoli, Italy.
L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences , Weigla 12, 53-114 Wrocław, Poland.
J Med Chem. 2017 Dec 14;60(23):9757-9768. doi: 10.1021/acs.jmedchem.7b01234. Epub 2017 Nov 14.
A semisynthetic strategy to obtain monophosphoryl lipid A derivatives equipped with clickable (azide, alkyne, double bond, or thiol precursor) moieties, starting from the native lipid A isolated from Escherichia coli, is presented. These lipid A derivatives can be conjugated with other interesting biomolecules, such as tumor-associated carbohydrate antigens (TACAs). In this way, the immunostimulant activity of monophosphoryl lipid A can significantly improve the immunogenicity of TACAs, thus opening access to potential self-adjuvant anticancer vaccine candidates. A monophosphoryl lipid A-Thomson-Friedenreich (TF) antigen conjugate was obtained to demonstrate the feasibility of this methodology, which stands as a valuable, rapid, and scalable alternative to the highly complex approaches of total synthesis recently reported to the same aim. A preliminary evaluation of the immunological activity of this conjugate as well as of other semisynthetic lipid A derivatives was also reported.
本文提出了一种半合成策略，该策略从大肠杆菌中分离出的天然脂质A出发，获得带有可点击（叠氮化物、炔烃、双键或硫醇前体）基团的单磷酸化脂质A衍生物。这些脂质A衍生物可以与其他有趣的生物分子共轭，如肿瘤相关碳水化合物抗原（TACAs）。通过这种方式，单磷酸化脂质A的免疫刺激活性可以显著提高TACAs的免疫原性，从而为潜在的自佐剂抗癌疫苗候选物开辟道路。制备了一种单磷酸化脂质A-汤姆森-弗里德赖希（TF）抗原共轭物，以证明该方法的可行性，该方法是最近报道的针对同一目标的高度复杂的全合成方法的一种有价值、快速且可扩展的替代方法。还报道了对该共轭物以及其他半合成脂质A衍生物的免疫活性的初步评估。
