Studies on vascular response to full superantigens and superantigen derived peptides: Possible production of novel superantigen variants with less vasodilation effect for tolerable cancer immunotherapy

• Published in: Biomedicine & pharmacotherapy 2019-07, Vol.115, p.108905-108905, Article 108905
• Main Authors: Bashraheel, Sara S., AlQahtani, Alanod D., Rashidi, Fatma B., Al-Sulaiti, Haya, Domling, Alexander, Orie, Nelson N., Goda, Sayed K.
• Format: Article
• Language: English
• Subjects: Animals; Escherichia coli - genetics; Hyperpolarization and antihypertensive drugs; Hypotension; Immunotherapy; Lymphocyte Activation - drug effects; Muscle, Smooth, Vascular - drug effects; Neoplasms - drug therapy; Neoplasms - immunology; Peptides - genetics; Peptides - pharmacology; Potassium channel; Sheep; Superantigen based peptides; Superantigenicity; Superantigens - genetics; Superantigens - pharmacology; T-cell activation; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Vasodilation; Vasodilation - drug effects
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2019.108905

[Display omitted] •The superantigens, SEA and SPEA caused dose-dependent relation of the ovine skeletal muscle (SKM).•The functional regions of SPEA that are involved in causing vasodilation and therefore, possible hypotension were identified.•The identified regions (peptides) could be used as antihypertensive therapeutics.•The above findings could pave the way for the production of superantigens with less or no hypotension side effect for tolerable cancer immunotherapy. Superantigens (SAgs) are a class of antigens that cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release and causing symptoms similar to sepsis, e.g. hypotension and subsequent hyporeactivity. We investigated the direct effect of SAgs on vascular tone using two recombinant SAgs, SEA and SPEA. The roles of Nitric Oxide (NO) and potentially hyperpolarization, which is dependent on the K+ channel activation, were also explored. The data show that SEA and SPEA have direct vasodilatory effects that were in part NO-dependent, but completely dependent on activation of K+ channels. Our work also identified the functional regions of one of the superantigens, SPEA, that are involved in causing the vasodilation and possible hypotension. A series of 20 overlapping peptides, spanning the entire sequence of SPEA, were designed and synthesized. The vascular response of each peptide was measured, and the active peptides were identified. Our results implicate the regions, (61–100), (101–140) and (181–220) which cause the vasodilation and possible hypotension effects of SPEA. The data also shows that the peptide 181–220 exert the highest vasodilation effect. This work therefore, demonstrates the direct effect of SAgs on vascular tone and identify the active region causing this vasodilation. We propose that these three peptides could be effective novel antihypertensive drugs. We also overexpressed, in E.coli, four superantigens from codon optimized genes.