ABSTRACT:The natural product cyclic peptide stylissatin A (1a), was reported to inhibit nitric oxide production in LPS-stimulated murine macrophage RAW 264.7 cells. In the current study, solidphase total synthesis of stylissatin A was performed by using a safety-catch linker and yielded the peptide with a trans-Pro 6 -Phe 7 linkage whereas the natural product is the trans rotamer at this position as evidenced by a marked difference in NMR chemical shifts. In order to preclude the possibility of 1b beingan epimer of the natural product, we repeated the synthesis using D-allo- production. The analogues 2-7 weakly inhibited NO . production, but strongly inhibited IL-2 cytokine production compared to synthetic peptide 1b. All analogues inhibited the proliferation of T-cells, with analogue 7 having the strongest effect. In the analogues, the Pro 6 residue was replaced by Glu/Ala and the SAR indicates that the nature of this residue plays a role in the biological function of these peptides.