Potent inhibition of the CD4-dependent T cell response by J2, a novel nonpeptide organic ligand of CD4 D1

作者：Xiao He; Feng Jian Nan; He Xin hua; Zhang Han; Zhang Jing Rui; Zhang Lei; Yu Ming; Huang Yi Fei; Li Song; Shen Bei Fen; Li Yan^*

来源：Molecular Immunology, 2007, 44(5): 784-795.

DOI：10.1016/j.molimm.2006.04.018

• CD4 D1
• non-peptidic small molecular organic inhibitors
• CD4-MHC II interaction
• CD4(+) T cell response
• Rosette formation
• immunosuppressive agents

The interaction between CD4 and major histocompatibility complex (MHC) class 11 proteins is critical for the activation of CD4(+) T cells, which are involved in transplantation reactions and a number of autoimmune diseases. It is known that the CD4 N-terminal immumoglobulin variable region-like domain (D I) is directed toward and reaching into the two membrane-proximal domains of the MHC class 11 molecule. Thus, compounds targeted to D1 would be expected to function as the inhibitors of the interaction of CD4 and class 11 MHC molecules. In this study, we used a computer-based design method to screen thousands of non-peptidic compounds in a molecular database and identified a group of compounds as potential ligands of CD4 D1. These small organic compounds were then synthesized and tested by actual biological assays. One of them, named J2, which possessed favorable activity, was obtained. Experimental data showed that J2 could specifically block stable CD4-MHC class 11 binding and elicit significant inhibition of immune responses in vitro and in vivo. All the results demonstrated the therapeutic potential of this compound as a novel immunosuppressive agent.

• 出版日期2007-2
• 单位中国人民解放军总医院