Structural modifications of ICAM-1 cyclic peptides to improve the activity to inhibit heterotypic adhesion of T cells.
Lymphocyte function-associated antigen-1 (LFA-1)/intercellular adhesion molecule-1 (ICAM-1) interaction plays an important role in the formation of the immunological synapse between T cells and antigen-presenting cells. Blocking of LFA-1/ICAM-1 interactions has been shown to suppress the progression of autoimmune diseases. cIBR peptide (cyclo(1,12)PenPRGGSVLVTGC) inhibits ICAM-1/LFA-1 interaction by binding to the I-domain of LFA-1. To increase the bioactivity of cIBR peptide, we systemically modified the structure of the peptide by (i) replacing the Pen residue at the N-terminus with Cys, (ii) cyclization using amide bond formation between Lys-Glu side chains, and (iii) reducing the peptide size by eliminating the C-terminal residue. We found that the activity of cIBR peptide was not affected by replacing Phe with Cys. Peptide cyclization by forming the Lys-Glu amide bond also increased the activity of cIBR peptide, presumably due to the resistance of the amide bond to the reducing nature of glutathione in plasma. We also found that a reduced derivative of cIBR with eight residues (cyclo(1,8)CPRGGSVC) has a bioactivity similar to that of the larger cIBR peptides. Our findings suggest that, by systemically modifying the structure of cIBR peptide, the biological activity of these derivatives can be optimized for future use to inhibit T-cell adhesion in in vivo models of autoimmune diseases.
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.
Iskandarsyah
Bimo A
BA
Tejo
Usman S F
US
Tambunan
Gennady
G
Verkhivker
Teruna J
TJ
Siahaan
D000938:Antigen-Presenting Cells; D001327:Autoimmune Diseases / Q000188:drug therapy; D002448:Cell Adhesion / Q000187:drug effects* / Q000276:immunology; D015195:Drug Design; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D016169:Lymphocyte Function-Associated Antigen-1; D010456:Peptides, Cyclic; D018799:Intercellular Adhesion Molecule-1