Novel peptide-based inhibitor for targeted inhibition of T cell function.

Abstract

Novel immunosuppressants are sought to overcome the side effects of currently used drugs. T cells play a central role in the functioning of the immune system; hence, drugs that specifically inhibit T cell function are expected to be better immunosuppressants with fewer side effects than the ones currently used. Peptides that interfere with crucial protein-protein interactions (PPIs) have been shown to influence cell physiology and have therapeutic potential. In this study, we designed a peptide, GVITAA, which specifically inhibits the function of lymphocyte-specific protein kinase (LCK), a signaling molecule that is mainly expressed in T cells and is responsible for positively regulating T cell function. Aspartate Histidine -Histidine Cysteine (DHHC21) -LCK is an important PPI present in T cells; DHHC21 interacts with LCK and targets the kinase to membrane rafts by adding a palmitoyl group. GVITAA is a ten amino acid peptide that interferes with the DHHC21-LCK interaction, prevents the membrane localization of LCK, and inhibits LCK-mediated initiation of complex signal transduction pathways required for T cell activation. In this study, we present evidence that the GVITAA peptide when conjugated with a cell-penetrating peptide-human immunodeficiency virus transactivator of transcription (TAT) and incubated with mouse T cells specifically inhibits LCK-mediated T cell receptor signaling, cytokine secretion, and T cell proliferation. This peptide does not affect other non-T cell functions and is non-toxic. A similar strategy was also tested and demonstrated in human peripheral T cells.