Study of disabling T-cell activation and inhibiting T-cell-mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidomimetics.
We designed a new class of aromatically modified exocyclic peptides based on the structure of CD4 by engineering one of the cysteine residues in a peptidomimetic derived from the CDR3 region of the CD4 molecule. All three species mediate inhibition of T-cell proliferation at concentrations ranging from 10 to 100 microM. The mimetics CD4-Cys and CD4-Met bind to sCD4 with affinities ranging from 1 to 2 microM, while CD4-Ser shows poor binding in radioisotope assay. Though these mimetics have similar structures, they exhibit different biochemical and biological functions. Activation of T-cells as measured by thymidine incorporation or IL-2 production revealed that CD4-Cys and CD4-Ser mimetics behave as classical antagonists. On the other hand, the CD4-Met species inhibited T-cell proliferation with an IC(50) of 30 microM but unexpectedly increased IL-2 secretion modestly at a less than 3 microM concentration. In experimental autoimmune encephalitis (EAE), CD4-Ser and CD4-Cys mimetics reduced the severity of EAE symptoms while the CD4-Met mimetic exacerbated the conditions. We propose that CD4-Cys and CD4-Ser are classical antagonists, but CD4-Met may possess properties of an inverse agonist. The structure-activity relationship of mimetics reveals that a minor change in the net hydropathic value is enough to alter the dynamic nature of the receptor-ligand complex.
Horie
Takeo
T
Department of Pathology and School of Medicine, University of Pensylvania, Philadelphia, Pennsylvania 19104, USA.
Shen
Yuan
Y
Kajino
Kiichi
K
Gaubin
Muriel
M
Bonomi
Giovanna
G
Mani
Jean-Claude
JC
Berezov
Alan
A
Piatier-Tonneau
Dominique
D
Guardiola
John
J
Hillard
Brendan
B
Rostami
Abdolmohamad
A
Greene
Mark
M
Murali
Ramachandran
R
D000818:Animals; D001709:Biotechnology; D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000378:metabolism; D003198:Computer Simulation; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008285:Major Histocompatibility Complex; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D008954:Models, Biological; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015704:CD4 Antigens; D022801:Complementarity Determining Regions; D007376:Interleukin-2; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell