We have reported previously the design of a RIAD (RI-anchoring disruptor) peptide that specifically displaces PKA (protein kinase A) type I from the AKAP (A-kinase-anchoring protein) ezrin, which is present in the immunological synapse of T-cells. This increases immune reactivity by reducing the threshold for activation and may prove a feasible approach for improving immune function in patients with cAMP-mediated T-cell dysfunction. However, the use of RIAD in biological systems is restricted by its susceptibility to enzymatic cleavage and, consequently, its short half-life in presence of the ubiquitous serum peptidases. In the present study, carefully selected non-natural amino acids were employed in the design of RIAD analogues with improved stability. The resulting peptidomimetics demonstrated up to 50-fold increased half-lives in serum compared with RIAD, while maintaining similar or improved specificity and potency with respect to disruption of PKA type I-AKAP interactions.