Potent inhibition of the CD4-dependent T cell response by J2, a novel nonpeptide organic ligand of CD4 D1.
The interaction between CD4 and major histocompatibility complex (MHC) class II 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 immunoglobulin variable region-like domain (D1) is directed toward and reaching into the two membrane-proximal domains of the MHC class II molecule. Thus, compounds targeted to D1 would be expected to function as the inhibitors of the interaction of CD4 and class II 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 II 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.
Xiao
He
H
Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road 27, 100850 Beijing, China.
Feng
Jian-Nan
JN
He
Xin-Hua
XH
Zhang
Han
H
Zhang
Jing-Rui
JR
Zhang
Lei
L
Yu
Ming
M
Huang
Yi-Fei
YF
Li
Song
S
Shen
Bei-Fen
BF
Li
Yan
Y
D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology; D008024:Ligands; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology
D000178:Acrylamides; D015704:CD4 Antigens; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007135:Immunoglobulin Variable Region; D007166:Immunosuppressive Agents; D007211:Indoles; D007376:Interleukin-2; D008024:Ligands; C517552:N-(6-methylamino-3-nitrophenyl)-3-(3-indolyl)acrylamide