Development of Clickable Monophosphoryl Lipid A Derivatives toward Semisynthetic Conjugates with Tumor-Associated Carbohydrate Antigens

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.

本研究报道了一种半合成策略，可从大肠杆菌（Escherichia coli）分离得到的天然脂质A出发，制备带有可点击化学官能团（叠氮基、炔基、双键或巯基前体）的单磷酰脂质A（monophosphoryl lipid A）衍生物。此类脂质A衍生物可与其他具有研究价值的生物分子结合，例如肿瘤相关糖类抗原（tumor-associated carbohydrate antigens, TACAs）。借助该策略，单磷酰脂质A的免疫刺激活性可显著增强TACAs的免疫原性，从而为开发潜在的自佐剂型抗癌疫苗候选物开辟了可行路径。本研究制备了单磷酰脂质A-汤姆森-弗里德赖希抗原（Thomson-Friedenreich antigen, TF）结合物，以验证该方法的可行性；相较于近期报道的针对同一研究目标的全合成复杂策略，该方法具备高效、快速且可规模化的优势，具有重要应用价值。本研究同时对该结合物及其他半合成脂质A衍生物的免疫活性进行了初步评价。