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.

A novel lipidic peptide with potential to promote balanced effector-regulatory T cell responses

“…Such studies could also help to resolve conflicting reports of large increases in IL-2 production with Lck knock-down 91 versus suppression of IL-2 production in the presence of SFK inhibitors 92 . Furthermore, it would be interesting to compare effects of IK14004 on phosphorylation of proximal signalling molecules involved in TCR signalling and cytokine production with data recently reported for a 10 mer peptide linked to a non-lipid cell-entry moiety 93 . These investigators incubated effector T cells with a peptide concentration much higher than that used in our study resulting in inhibition of both IL-2 and IFN-γ 93 .…”

“…Furthermore, it would be interesting to compare effects of IK14004 on phosphorylation of proximal signalling molecules involved in TCR signalling and cytokine production with data recently reported for a 10 mer peptide linked to a non-lipid cell-entry moiety 93 . These investigators incubated effector T cells with a peptide concentration much higher than that used in our study resulting in inhibition of both IL-2 and IFN-γ 93 . Such comparisons could shed light on how Lck regulates the discrimination between strong and weak agonists at the TCR.…”

Bitter-RF: A random forest machine model for recognizing bitter peptides

“…At present, computational methods have been carried out to study peptides (13,14). Models based on the quantitative structure of bitter taste relationship (QSBR), including multiple linear regression, the support vector machine (SVM), and artificial neural network (ANN), have been used to predict bitter peptides (2,(15)(16)(17)(18)(19)(20)(21).…”