Synthesis And Immunological Evaluation Of C-Glycoside Analogues Of NKT Cell Agonists

Adjuvants are one of the important components of vaccines.α-GalCer can stimulate NKT cells to rapidly trigger the release of cytokines and play a supporting role in the acquired immune response.In recent years,it has become a research hotspot of vaccine adjuvants.Our previous work has shown that embedding α-GalCer in a liposome nicotine vaccine can efficiently elicit an antibody immune response against nicotine.However,α-GalCer stimulates NKT cells to secrete both Thl and Th2 cytokines,and the opposite immune mode limits the clinical therapeutic effect.As a Th1 type immunostimulant,α-C-GalCer can continuously stimulate NKT cells and exhibit immunological effects superior to α-GalCer in some disease models.Therefore,we envisage that the introduction of α-C-GalCer and its C-glycoside analogs can elicit an anti-nicotine immune response more efficiently.This paper is divided into three chapters.The main contents of each chapter are as follows:The first chapter briefly introduces the characteristics,functions and mechanisms of NKT cells;it summarizes the typical Thl and Th2 types of NKT cell agonists.In addition,the pharmacological effects of nicotine-induced addiction and the current status of research on nicotine vaccine are summarized.Finally,it is designed to synthesizeα-C-Galcer and C-glycoside analogues,self-assemble with nicotine antigen,developing a simple structure,easy to prepare,and can obtain a synthetic vaccine that efficiently elicits an immune response against nicotine antibodies.The second chapter develops a new synthetic route to construct C-glycoside analogues.Key steps in this synthetic route include hydroboration-oxidation,Olefin Cross-Metathesis reaction,Sharpless asymmetric epoxidation,and epoxide-opening by rings.The stereochemistry of the epoxide-opening was determined by Mosher amide,excluding the possibility of neighboring groups participating in the configuration reversal.The third chapter evaluates the anti-nicotine immunoreactivity of α-C-GalCer and C-glycoside analogues in nicotine liposome vaccines,including IgM and IgG antibodies and IgG subtype antibody titers,cytokine concentrations,antibody affinity,and animal behavior experiments.The results indicate that C-glycoside agonists can elicit an anti-nicotine antibody immunoreactivity similar to α-GalCer and exhibit a Thl bias.In summary,we have developed a new route for the synthesis of α-C-GalCer and C-glycoside analogues and evaluated their adjuvant activity in liposomal nicotine vaccines,which provides a theoretical basis for further development of NKT cell C-glycoside analogues.