Abstract
The interaction between CD4 and major histocompatibility complex class II proteins provides a critical co-receptor function for the activation of CD4(+) T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC' surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions.
Highlights
The interaction between CD4 and major histocompatibility complex class II proteins provides a critical coreceptor function for the activation of CD4؉ T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses
A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions
CD4ϩ T cells participate in the pathogenesis of a number of immune-based human conditions, including autoimmune diseases, allogenic organ transplant rejection, and graft versus host disease (GVHD) following allogenic bone marrow transplantation
Summary
The interaction between CD4 and major histocompatibility complex class II proteins provides a critical coreceptor function for the activation of CD4؉ T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions. Small molecular inhibitors of the CD4-MHC class II interaction could potentially block the undesirable activation of CD4ϩ T cells and could serve as effective immunosuppressive agents.
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