Thioamides: synthesis, stability, and immunological activities of thioanalogues of Imreg. Preparation of new thioacylating agents using fluorobenzimidazolone derivatives.
Imreg (Tyr1-Gly2-Gly3) is a well-known immunostimulant. However, it possesses a short half-life. Stabilized analogues of Imreg were prepared by a regioselective insertion in which peptide bonds at position 1,2 or 2,3 were replaced by thioamide linkages. This was achieved by using new thioacylating agents based on thioacyl-fluoro-N-benzimidazolone. The synthesis and properties of these reagents are described herein. This peptide modification enhanced significantly the half-life of the thioanalogues relative to Imreg in blood. The thioanalogues and Imreg were tested in vitro in T and B cell proliferation assays and for their ability to stimulate cytotoxic T-lymphocytes (CTLs). Only thiotyrosyl glycyl glycine 11 displayed some activity as evidenced by a weak stimulation of CTLs. On the basis of this activity and the increased stability, an in vivo immunological evaluation was undertaken. Immunophenotyping of 11 revealed a significant increase in activated CTL and NK cell populations in the spleen. This expansion was also accompanied by a significant stimulation of NK cells and the B cell proliferative response. Thioanalogues of Imreg were generally nontoxic, as exemplified by 11. The latter is a promising immunostimulant which may be targeted for cancer and viral infections, where CTLs and NK cells play an important role, or as a vaccine adjuvant where stimulation of antibody-producing B cells is important.
Zacharie
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B
BioChem Pharma Inc., 275 Armand-Frappier Blvd., Laval, Quebec, Canada, H7V 4A7.
Lagraoui
M
M
Dimarco
M
M
Penney
C L
CL
Gagnon
L
L
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004355:Drug Stability; D010450:Endopeptidases / Q000737:chemistry; D005260:Female; D016130:Immunophenotyping; D007668:Kidney / Q000201:enzymology / Q000648:ultrastructure; D007694:Killer Cells, Natural / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000201:enzymology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D009842:Oligopeptides; C119481:thiotyrosyl-glycyl-glycine; C044757:tyrosyl-glycyl-glycine; D010450:Endopeptidases