Enhanced phagocytosis activity of cyclic analogs of tuftsin

Cyclic analogs of the physiological immunostimulating peptide tuftsin (Thr-Lys-Pro-Arg), cyclo(Thr-Lys-Pro-Arg-Gly) (ctuf-G) and cyclo(Thr-Lys-Pro-Arg-Asp) (ctuf-D), were synthesized based on molecular modeling studies, and assayed for the ability to stimulate phagocytosis by human polymorphonuclear leukocytes. As predicted, the synthesis of ctuf-D resulted in two isomers with the correct molecular mass and amino acid composition. In phagocytosis assays, tuftsin, ctuf-G and two isomers of ctuf-D showed the usual bell-shaped activity profiles. The optimum concentration of ctuf-G was 50-fold less than that of tuftsin, whereas the degree of stimulation was similar. One isomer of ctuf-D was almost inactive, and the other ctuf-D exhibited the same degree of phagocytosis as tuftsin but its optimum concentration was 5-fold lower. The enhanced potency of ctuf-G and one isomer of ctuf-D may be due to conformational effects and/or to the possibility that these cyclic peptides are resistant to proteolytic degradation.