Bioactive peptide design based on protein surface epitopes. A cyclic heptapeptide mimics CD4 domain 1 CC' loop and inhibits CD4 biological function.
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.
Satoh
T
T
Kimmel Cancer Institute, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Aramini
J M
JM
Li
S
S
Friedman
T M
TM
Gao
J
J
Edling
A E
AE
Townsend
R
R
Koch
U
U
Choksi
S
S
Germann
M W
MW
Korngold
R
R
Huang
Z
Z
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry* / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D003196:Computer Graphics; D015195:Drug Design; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000503:physiopathology; D000939:Epitopes / Q000737:chemistry*; D005260:Female; D005802:Genes, MHC Class II; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D016038:Skin Transplantation / Q000276:immunology
D015704:CD4 Antigens; D000939:Epitopes; D009842:Oligopeptides; D010456:Peptides, Cyclic