Design, Synthesis Of CD4 Protein Inhibitors

In 1945, Sir Peter Medawar performed skin transplantations in rabbits proving that rejection was an immunemediated response. It makes the foundation of transplantation. In 1954, the first kidney transplantation was succeeded. Transplantation has been an effective remedy for failing organs; however, a balance between prevention of acute rejection and immunosuppressant induced toxicity remains elusive. Organ transplantation from a genetically disparate donor induces an immune response in the recipient by donor antigens. An uncontrolled cumulative effect of these responses may jeopardize the recipient's life and eventually destroy the grafted tissue.The cascade of the acute rejection process begins with the presentation of donor alloantigens to recipient T cells through antigen presenting cells(APC) or by a direct mechanism. Over time the grafted organ becomes less immunogeneic. More and more patients take the organ transplatation and become healthy. After the transplatation, most of the patients need to take the immunosuppressant agents to inhibit the transplatation rejection. It becomes more and more important to develop new immunosuppressant agents with potent effect and lower toxicity.The interaction between CD4 and major histocompatibility complex(MHC) classâ…¡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 classâ…¡molecule. Thus, compounds targeted to D1 would be expected to function as the inhibitors of the interaction of CD4 and classâ…¡MHC molecules. In recent studies, lots of small organic compounds were 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 classâ…¡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 immuno- suppressive agent.In the thesis, based on the structure of J2, we designed novel CD4 inhibitors by traditional method. These compounds have similar geometric figures with J2.The method which we used included dissection, association, bioisosterism and local manipulation, such as adding or deleting groups. Finally, we synthsized 20 new compounds, which have been tested their immunity suppression activity.