Synthesis and biological activity of cyclolinopeptide A analogues modified with γ3-bis(homophenylalanine)

Natural cyclic polypeptides as vital phytochemical constituents from seeds of selected medicinal plants

“…All analogs were modified with γ 3 ‐hhPhe residue at position 3 or 4 as well as at both positions 3 and 4. [ 86 ]…”

“…Linear peptides did not inhibit mitogen‐induced PBMC (peripheral blood mononuclear cell) proliferation, whereas cyclic ones inhibited the proliferation in a dose‐dependent manner. [ 86 ]…”

“…The CLA analog with single modification S‐γ 3 ‐hhPhe 3 is a mixture of two isomers and the major isomer (89%) contains all peptide bonds of the trans geometry. [ 86 ]…”

Effects of Modifications on the Immunosuppressive Properties of Cyclolinopeptide A and its Analogs in Animal Experimental Models

“…The peptide completely blocked proliferation of mouse splenocytes to mitogens, albeit only at 100 µg/ml concentration, thus being much less potent in comparison with CsA used as a reference drug. Very promising suppressive analogs were also obtained by modification of linear and cyclic CLA with S or R-γ 3 -bis(homophenylalanine) in positions 8 or 9, or both [16]. Only cyclic peptides inhibited the proliferative response of PBMC to phytohemagglutinin (PHA) and exhibited a dose dependent toxicity except a peptide substituted with S-ɣ 3 hhPhe 9 .…”

“…Another group of researchers [26] confirmed that this type of interaction is weak since the inhibition of calcineurin activity, important in T cell signaling and proliferation [27] required 10 x higher concentration of CLA than for CsA or tacrolimus. Strong inhibition of mitogen induced proliferation of PBMC by CLA analogs was associated with significant changes in expression of cell signaling molecules in Jurkat T cells [17,18], such as block of caspase 3 responsible for activation of T cells and IL-2 production [28] and increase of Fas [16] involved in apoptosis [27]. In turn, the mechanism of action of cyclic tetrapeptide c(Pro-Pro-β 3 hPhe-Phe-) was clearly associated with its effects on prostanoid activity [20].…”