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 μM. The mimetics CD4-Cys and CD4-Met bind to sCD4 with affinities ranging from 1 to 2 μM, 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 5 0 of 30 μM but unexpectedly increased IL-2 secretion modestly at a less than 3 μM 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.