Study of disabling T-cell activation and inhibiting T-cell-mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidomimetics.

Authors

• Takeo Horie
• Yuan Shen
• Kiichi Kajino
• Muriel Gaubin
• Giovanna Bonomi
• Jean-Claude Mani
• Alan Berezov
• Dominique Piatier-Tonneau
• John Guardiola
• Brendan Hillard
• Abdolmohamad Rostami
• Mark Greene
• Ramachandran Murali

Publication/Presentation Date

10-1-2002

Abstract

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.

Volume

73

Issue

2

First Page

93

Last Page

103

ISSN

0014-4800

Published In/Presented At

Horie, T., Shen, Y., Kajino, K., Gaubin, M., Bonomi, G., Mani, J. C., Berezov, A., Piatier-Tonneau, D., Guardiola, J., Hillard, B., Rostami, A., Greene, M., & Murali, R. (2002). Study of disabling T-cell activation and inhibiting T-cell-mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidomimetics. Experimental and molecular pathology, 73(2), 93–103. https://doi.org/10.1006/exmp.2002.2444

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

12231211

Department(s)

Administration and Leadership

Document Type

Article