title: Cyclization enhances function of linear anti-arthritic peptides.
abstract: This study describes the biophysical and immunomodulatory features of a cyclic peptide termed C1 which consists of alternating d-, l-amino acids and is capable of inhibiting IL-2 production in vitro and reducing the induction and extent of T-cell mediated inflammation in animal models. Solid-state nuclear magnetic resonance demonstrates that the peptide orders the lipid bilayer, suggesting a transmembrane orientation, and this is supported by surface plasmon resonance indicating strong binding affinity of C1 to model membranes. In vitro cell viability and proliferation assays show that C1 does not disrupt the integrity of cell surface membranes. Permeation studies of C1 and analogs across human epidermis cells show that the stability and skin permeability are enhanced by cyclization. Treatment with C1 in an asthma and in an arthritis animal model resulted in a suppressed immune response. Cyclization may be a useful means of enhancing biological linear peptide activity and improving delivery.
authors.affiliation: Rheumatology Department, The University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ali
authors.affiliation: Rheumatology Department, The University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Amon
authors.affiliation: Rheumatology Department, The University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Vera
authors.initials: V
authors.lastname: Bender
authors.affiliation: Rheumatology Department, The University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bolte
authors.affiliation: School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne VIC 3010, Australia.
authors.forename: Frances
authors.initials: F
authors.lastname: Separovic
authors.affiliation: School of Pharmacy, CHIRI, Curtin University, Perth, WA 6102, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Benson
authors.affiliation: Rheumatology Department, The University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia. Electronic address: nicholas.manolios@sydney.edu.au.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Manolios
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D017951:Antigen Presentation; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002460:Cell Line; D003500:Cyclization; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D006825:Hybridomas; D066298:In Vitro Techniques; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D010456:Peptides, Cyclic
keywords: 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine; 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol; 3-(N-morpholino) propane sulfonic acid; AA; ACD; Arthritis; Asthma; At-Column Dilution; BALF; C1; C1-L; CP; DIEA; DMF; DMPC; DMPG; DMSO; FDPP; HEPES; IL; Inflammation; MOPS; MTB; Mycobacterium tuberculosis; N,N-diisopropylethylamine; N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid; NMR; PBL; PG; PMA; Peptides; Phorbol 12-myristate 13-acetate (PMA); SEA; SPR; SUV; T cell antigen receptor; T cells; TCR; TFA; amino acid; bronchoalveolar lavage fluid; core peptide; cyclic peptide 1; dimethylformamide; dimethylsulfoxide; interleukin; linear sequence of C1; nuclear magnetic resonance; pentafluorophenyl diphenylphosphinate; peripheral blood lymphocyte; propylene glycol; small unilamellar vesicles; staphylococcal enterotoxin A; surface plasmon resonance; trifluoroacetic acid.