title: Lipidation and glycosylation of a T cell antigen receptor (TCR) transmembrane hydrophobic peptide dramatically enhances in vitro and in vivo function.
abstract: A T cell antigen receptor (TCR) transmembrane sequence derived peptide (CP) has been shown to inhibit T cell activation both in vitro and in vivo at the membrane level of the receptor signal transduction. To examine the effect of sugar or lipid conjugations on CP function, we linked CP to 1-aminoglucosesuccinate (GS), N-myristate (MYR), mono-di-tripalmitate (LP1, LP2, or LP3), and a lipoamino acid (LA) and examined the effects of these compounds on T cell activation in vitro and by using a rat model of adjuvant-induced arthritis, in vivo. In vitro, antigen presentation results demonstrated that lipid conjugation enhanced CP's ability to lower IL-2 production from 56.99%+/-15.69 S.D. observed with CP, to 12.08%+/-3.34 S.D. observed with LA. The sugar conjugate GS resulted in only a mild loss of in vitro activity compared to CP (82.95%+/-14.96 S.D.). In vivo, lipid conjugation retarded the progression of adjuvant-induced arthritis by approximately 50%, whereas the sugar conjugated CP, GS, almost completely inhibited the progression of arthritis. This study demonstrates that hydrophobic peptide activity is markedly enhanced in vitro and in vivo by conjugation to lipids or sugars. This may have practical applications in drug delivery and bioavailability of hydrophobic peptides.
authors.affiliation: Department of Rheumatology, Westmead Hospital, Westmead, NSW. 2145, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Amon
authors.forename: Marina
authors.initials: M
authors.lastname: Ali
authors.forename: Vera
authors.initials: V
authors.lastname: Bender
authors.forename: Yiu-Ngok
authors.initials: YN
authors.lastname: Chan
authors.forename: Istvan
authors.initials: I
authors.lastname: Toth
authors.forename: Nicholas
authors.initials: N
authors.lastname: Manolios
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D006031:Glycosylation; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008055:Lipids / Q000737:chemistry; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D017252:CD3 Complex; D003432:Cross-Linking Reagents; D004768:Enterotoxins; D007376:Interleukin-2; D008055:Lipids; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C026066:enterotoxin A, Staphylococcal; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate