Targeting ICAM-1/LFA-1 interaction for controlling autoimmune diseases: designing peptide and small molecule inhibitors.
This review describes the role of modulation of intracellular adhesion molecule-1 (ICAM-1)/leukocyte function-associated antigen-1 (LFA-1) interaction in controlling autoimmune diseases or inducing immunotolerance. ICAM-1/LFA-1 interaction is essential for T-cell activation as well as for migration of T-cells to target tissues. This interaction also functions, along with Signal-1, as a co-stimulatory signal (Signal-2) for T-cell activation, which is delivered by the T-cell receptors (TCR)-major histocompatibility complex (MHC)-peptide complex. Therefore, blocking ICAM-1/LFA-1 interaction can suppress T-cell activation in autoimmune diseases and organ transplantation. Many types of inhibitors (i.e. antibodies, peptides, small molecules) have been developed to block ICAM-1/LFA-1 interactions, and some of these molecules have reached clinical trials. Peptides derived from ICAM-1 and LFA-1 sequences have been shown to inhibit T-cell adhesion and activation. In addition, these inhibitors have been useful in elucidating the mechanism of ICAM-1/LFA-1 interaction. Besides binding to LFA-1, the ICAM-1 peptide can be internalized by LFA-1 receptors into the cytoplasmic domain of T-cells. Therefore, this ICAM-1 peptide can be utilized to selectively target toxic drugs to T-cells, thus avoiding harmful side effects. Finally, bi-functional inhibitory peptide (BPI), which is made by conjugating the antigenic peptide and an LFA-1 peptide, can alter the T-cell commitment from T-helper-1 (Th1) to T-helper-2 (Th2)-like cells, suggesting that this peptide may have a role in blocking the formation of the "immunological synapse."
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, KS 66047, USA.
Meagan E
ME
Anderson
Teruna J
TJ
Siahaan
D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015195:Drug Design; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects
D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D018799:Intercellular Adhesion Molecule-1