title: Synthesis and biological activity of cyclolinopeptide A analogues modified with γ(3)-bis(homophenylalanine).
abstract: Cyclolinopeptide A, naturally occurring immunomodulatory nonapeptide, was modified with S or R-γ(3)-bis(homophenylalanine) in positions 3 or 4, or both 3 and 4. The replacement of one or both Phe residues by γ(3)-hhPhe led to decrease of their conformational flexibility in the analogues in comparison to CLA. All cyclic peptides, except 11, exist as isomers with the cis Pro-Pro peptide bond. Cyclic peptide 11 with single modification S-γ(3)-hhPhe(4) exists as a mixture of two isomers and the major isomer (89%) contains all peptide bonds of the trans geometry. The peptides were subjected to several immunological tests in vitro and in vivo. Linear peptides 1-8, precursors of CLA analogues 9-16, were not toxic against human peripheral blood mononuclear cells (PBMC) but cyclic analogues showed dose-dependent toxicity with exception of peptide 11. Linear peptides did not inhibit mitogen-induced PBMC proliferation whereas cyclic ones inhibited the proliferation in a dose-dependent manner. The actions of linear and cyclic peptides with regard to lipopolysaccharide (LPS) -induced tumour necrosis factor alpha (TNF α) production in whole human blood cultures were differential but particularly suppressive in the case of linear compound 6. Therefore, for in vivo tests compounds 6 and 11 were selected. The compounds showed comparable, suppressive actions in induction and effector phases of delayed type hypersensitivity as well as in the carrageenan-induced foot pad edema in mouse models. In summary, linear peptide 6 and cyclic peptide 11 are attractive as potential immune suppressor drugs.
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Łódź, Żeromskiego 116, 90-924, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Jędrzejczak
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Łódź, Żeromskiego 116, 90-924, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Hrynczyszyn
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Science, R. Weigla 12, 53-114 Wroclaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Artym
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Science, R. Weigla 12, 53-114 Wroclaw, Poland.
authors.forename: Maja
authors.initials: M
authors.lastname: Kocięba
authors.affiliation: Institute of Immunology and Experimental Therapy, Polish Academy of Science, R. Weigla 12, 53-114 Wroclaw, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Zimecki
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Łódź, Żeromskiego 116, 90-924, Poland; Peptaderm Ltd., Rydygiera 8, 01-793 Warsaw, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Zabrocki
authors.affiliation: Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Łódź, Żeromskiego 116, 90-924, Poland. Electronic address: stefan.jankowski@p.lodz.pl.
authors.forename: Stefan
authors.initials: S
authors.lastname: Jankowski
mesh_terms: D000818:Animals; D002351:Carrageenan; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007165:Immunosuppression Therapy; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D010456:Peptides, Cyclic; C055018:cyclolinopeptide A; C000598939:gamma(3)-bis(homophenylalanine); D010649:Phenylalanine; D002351:Carrageenan
keywords: Cyclolinopeptide A; Gamma amino acids; Immune response; Immunosuppression; Proliferation; TNF-α