BIOACTIVE PEPTIDE DESIGN BASED ON PROTEIN SURFACE EPITOPES - A CYCLICHEPTAPEPTIDE MIMICS CD4 DOMAIN-1 CC'-LOOP AND INHIBITS CD4 BIOLOGICALFUNCTION

The interaction between CD4 and major histocompatibility complex class II proteins provides a critical coreceptor function for the activatio n of CD4(+) T cells implicated in the pathogenesis of a number of auto immune diseases and transplantation responses. A small synthetic cycli c heptapeptide was designed and shown by high resolution NMR spectrosc opy to closely mimic the CD4 domain 1 CC' surface loop. This peptide e ffectively blocked stable CD4-major histocompatibility complex class I I interaction, possessed significant immunosuppressive activity in vit ro and in. vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a nov el immunosuppressive agent and suggest a general strategy of drug desi gn by using small conformationally constrained peptide mimics of prote in surface epitopes to inhibit protein interactions and biological fun ctions.