Immunosuppressive analogues of hexapeptide Tyr-Val-Pro-Leu-Phe-Pro, an immune system stimulant.
It was found that substitution of Val2 and/or Leu4 residue in a hexapeptide Tyr-Val-Pro-Leu-Phe-Pro (I) transforms this peptide immunostimulant into analogues possessing the immunosuppressor activity--Tyr-Gly-Pro-Leu-Phe-Pro (II), Tyr-Val-Pro-Gly-Phe-Pro (III), and Tyr-Gly-Pro-Gly-Phe-Pro (IV). Biological effects of peptides I-IV were studied using PFC (plaque forming cell) test, GvH (graft vs host) reaction in mice, and ARFC (autologous rosette forming cell) test. The strongest immunosuppressor activity was observed for III--in this case the immunosuppressor effect was observed even in PFC test in vitro in which II and IV showed no such activity. These results suggest that simultaneous presence of both Val2 and Leu4 residues is necessary for the generation of immunostimulation. The CD study of I-IV in methanol solution suggests that the conformational preferences of II-IV change towards stabilization of the beta-turn structure, whereas in the case of I the gamma-turn on Leu4 and cis' orientation of the Pro3 carbonyl (distorted beta-turn of type I) was found as the preferred conformation. Competition in biological effects observed for I and III in PFC in vitro test suggests that these analogues may interact with the same cellular receptor. Drastic changes in the activity which accompany changes in the sequence are discussed in the terms of our stereochemical hypothesis.
Siemion
I Z
IZ
Institute of Chemistry, University of Wrocław, Poland.
Kubik
A
A
Lisowski
M
M
Szewczuk
Z
Z
Zimecki
M
M
Wieczorek
Z
Z
D000276:Adjuvants, Immunologic / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002855:Chromatography, Thin Layer; D002942:Circular Dichroism; D005260:Female; D006087:Graft vs Host Reaction; D006462:Hemolytic Plaque Technique; D007166:Immunosuppressive Agents; D007930:Leucine / Q000737:chemistry; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D012397:Rosette Formation; D013329:Structure-Activity Relationship; D014633:Valine / Q000737:chemistry
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D009842:Oligopeptides; C058579:proline-rich polypeptide, C-terminal hexapeptide; C071503:tyrosyl-glycyl-prolyl-leucyl-phenylalanyl-proline; C071504:tyrosyl-valyl-prolyl-glycyl-phenylalanyl-proline; C071502:tyrosyl-glycyl-prolyl-glycyl-phenylalanyl-proline; D007930:Leucine; D014633:Valine