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

Bashraheel, Sara S.; Al-Qahtani, Alanod; Rashidi, Fatma B.; Al-Sulaiti, Haya; Dömling, Alexander; Orie, Nelson N.; Goda, Sayed K.

doi:10.1016/j.biopha.2019.108905

Cited by 7 publications

(8 citation statements)

References 34 publications

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“…The role of superantigens in sepsis, a leading cause of death listed by the WHO, makes them an important target for toxic-shock syndrome ( 154 ). Several short peptide regions (~40 residues) from SEA and SPEA have been identified as causes of vasodilation ( 155 ), suggesting an application in the development of antihypertension drugs.…”

Section: Clinical Usagementioning

confidence: 99%

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

2021

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Superantigens are unconventional antigens which recognise immune receptors outside their usual recognition sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulins on B-cells, affecting opsonisation, IgG-mediated phagocytosis, and driving apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology.

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Section: Clinical Usagementioning

confidence: 99%

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

2021

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“…One of the damages bacterial superantigens can cause is severe hypotension, possibly leading to the patient’s death. Our previous work [ 54 ] identified the regions of SPEA involved in causing vasodilation and possible hypotension. We carried out the work by designing and synthesizing a series of 20 overlapping peptides spanning the entire sequence of SPEA.…”

Section: Discussionmentioning

confidence: 99%

Novel SPEA Superantigen Peptide Agonists and Peptide Agonist-TGFαL3 Conjugate. In Vitro Study of Their Growth-Inhibitory Effects for Targeted Cancer Immunotherapy

Bashraheel

Goda

2023

IJMS

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Bacterial superantigens (SAgs) are effective T-cell stimulatory molecules that lead to massive cytokine production. Superantigens crosslink between MHC class II molecules on the Antigen Presenting Cells (APC) and TCR on T-cells. This enables them to activate up to 20% of resting T cells, whilst conventional antigen presentation results in the activation of 0.001–0.0001% of the T cell population. These biological properties of superantigens make them attractive for use in immunotherapy. Previous studies have established the effectiveness of superantigens as therapeutic agents. This, however, was achieved with severe side effects due to the high lethality of the native toxins. Our study aims to produce superantigen-based peptides with minimum or no lethality for safer cancer treatment. In previous work, we designed and synthesized twenty overlapping SPEA-based peptides and successfully mapped regions in SPEA superantigen, causing a vasodilatory response. We screened 20 overlapping SPEA-based peptides designed and synthesized to cover the whole SPEA molecule for T-cell activation and tumor-killing ability. In addition, we designed and synthesized tumor-targeted superantigen-based peptides by fusion of TGFαL3 either from the N′ or C′ terminal of selected SPEA-based peptides with an eight-amino acid flexible linker in between. Our study identified parts of SPEA capable of stimulating human T-cells and producing different cytokines. We also demonstrated that the SPEA-based peptide conjugate binds specifically to cancer cells and can kill this cancer. Peptides induce T-cell activation, and tumor killing might pave the way for safer tumor-targeted superantigens (TTS). We proposed the combination of our new superantigen-based peptide conjugates with other immunotherapy techniques for effective and safer cancer treatment.

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“…Tissues were collected immediately following euthanasia and were taken to the laboratory in normal physiological salt solution of the following composition: NaCl (112 mM), KCl (5 mM), CaCl 2 (1.8 mM), MgCl 2 (1 mM), NaHCO 3 (25 mM), KH 2 PO 3 (0.5 mM), NaH 2 PO 3 (0.5 mM) and glucose (10 mM) and gassed with 95% O 2 /5% CO 2 to pH 7.4. Segments (2 mm long) of the isolated arterioles were mounted in isometric myographs (510A; Danish Myo Technology A/S, Hinnerup, Denmark) and were pre-tensioned to an equivalent of 100 mm Hg using an automatic normalization protocol, which also determined the vessels’ luminal diameter as previously described [ 17 , 18 ]. The mounted segments were continuously aerated at 37°C and allowed an equilibration period of at least 1 h before experiments.…”

Section: Methodsmentioning

confidence: 99%

Downregulation of CYP17A1 By 20-hydroxyecdysone: Plasma Progesterone and Its Vasodilatory Properties

et al. 2022

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Aim: To investigate the effect of 20-hydroxyecdysone on steroidogenic pathway genes and plasma progesterone, and its potential impact on vascular functions. Methods: Chimeric mice with humanized liver were treated with 20-hydroxyecdysone for 3 days, and hepatic steroidogenic pathway genes and plasma progesterone were measured by transcriptomics and GC–MS/MS, respectively. Direct effects on muscle and mesenteric arterioles were assessed by myography. Results: CYP17A1 was downregulated in 20-hydroxyecdysone-treated mice compared with untreated group (p = 0.04), with an insignificant increase in plasma progesterone. Progesterone caused vasorelaxation which was blocked by 60 mM KCl, but unaffected by nitric oxide synthase inhibition. Conclusion: In the short term, 20-hydroxyecdysone mediates CYP17A1 downregulation without a significant increase in plasma progesterone, which has a vasodilatory effect involving inhibition of voltage-dependent calcium channels, and the potential to enhance 20-hydroxyecdysone vasorelaxation.

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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

Cited by 7 publications

References 34 publications

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

Superantigen Recognition and Interactions: Functions, Mechanisms and Applications

Novel SPEA Superantigen Peptide Agonists and Peptide Agonist-TGFαL3 Conjugate. In Vitro Study of Their Growth-Inhibitory Effects for Targeted Cancer Immunotherapy

Downregulation of CYP17A1 By 20-hydroxyecdysone: Plasma Progesterone and Its Vasodilatory Properties

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