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.
Gene polymorphism among humans is one of the factors governing individual's susceptibility and resistance to various diseases including cancer. DNA repair enzymes play an important role in protecting our genome from various mutagens and preventing cancer. The role of DNA repair enzyme Apurinic/Apyrimidinic endodeoxyribonuclease 1 (Apex 1) in cancer has been very well documented. Using genomic DNA, Apex 1 coding region of 76 patients (n = 76) with head and neck cancer were amplified and sequenced to detect variations in the sequence. Of 76 patients, 1 patient with heterozygous novel Apex 1 variant (Glu87Gln) was identified. A comparative analysis of wild type and variant protein using in silico approach was performed to understand the difference in the structure and the function. This further revealed that the variant had a slight impact on the structure, which affected the stability and function of the protein. Using the state-of-the-art Molecular dynamic simulation analysis, we observed a loss in number of hydrogen bonds and salt bridge with a substitution of Gln for Glu at Position 87. This could be a possible reason behind the loss of stability/function of the protein. This study revealed a new variant of the Apex 1 gene; further studies will lead to the novel roles played by the variant Apex 1 protein in cause, disease progression, and response to the treatment in patients with cancer with Glu87Gln variant.
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