A Small-Molecule Inhibitor to the Cytokine Interleukin-4

Quinnell, Sean P.; Leifer, Becky; Nestor, Stephen T; Tan, Ker Sin; Sheehy, Daniel; Ceo, Luke M.; Doyle, Shelby K.; Koehler, Angela N.; Vegas, Arturo J.

doi:10.1021/acschembio.0c00615

Cited by 8 publications

(4 citation statements)

References 45 publications

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“…To validate the software efficiency, we selected compound 52 and reparixin, which are known to inhibit IL-4 and IL-8, respectively, and performed molecular docking as controls. [ 21 , 22 ]…”

Section: Methodsmentioning

confidence: 99%

A New Investigation into the Molecular Mechanism of Andrographolide towards Reducing Cytokine Storm

Alzahrani

2022

Molecules

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Cytokine storm is a condition in which the immune system produces an excessive number of inflammatory signals, which can result in organ failure and death. It is also known as cytokine release syndrome, CRS, or simply cytokine storm, and it has received a lot of attention recently because of the COVID-19 pandemic. It appears to be one of the reasons why some people experience life-threatening symptoms from COVID-19, a medical condition induced by SARS-CoV-2 infection. In situations where natural substances can be exploited as therapeutics to reduce cytokine storm, the drug development process has come to the rescue. In the present study, we tested the potentiality of Andrographolide, labdane diterpenoid targeting several key cytokines that are secreted as a result of cytokine storm. We used molecular docking analyses, molecular dynamics simulations, and pharmacokinetic properties to test the stability of the complexes. The compound’s binding energy with some cytokines was over −6.5 Kcal/mol. Furthermore, a post-molecular dynamics (MD) study revealed that Andrographolide was extremely stable with these cytokines. The compound’s pharmacokinetic measurements demonstrated excellent properties in terms of adsorption, distribution, metabolism, and excretion. Our research revealed that this compound may be effective in lowering cytokine storm and treating severe symptoms.

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Section: Methodsmentioning

confidence: 99%

A New Investigation into the Molecular Mechanism of Andrographolide towards Reducing Cytokine Storm

Alzahrani

2022

Molecules

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“…Compound‐52 (2‐amino‐4‐(3,4 dihydroxyphenyl)‐6‐(4‐fluorophenyl) nicotinonitrile) was the most promising hit obtained from a screen of 50,000 drugs using a small molecule microarray (SMM). Although its binding affinity for IL‐4 is only 1.8 μM, Compound‐52 was found to be effective in abolishing IL‐4 signaling in cellular assays 293 . There have also been efforts to develop designed ankyrin repeat proteins (DARPins) against IL‐4 and IL‐13.…”

Section: Il‐4/il‐13 Pathway Antagonistsmentioning

confidence: 99%

“…Although its binding affinity for IL-4 is only 1.8 μM, Compound-52 was found to be effective in abolishing IL-4 signaling in cellular assays. 293 There have also been efforts to develop designed ankyrin repeat proteins (DARPins) against IL-4 and IL-13. An anti-IL-4 DARPin denoted 44C12V5 binds the A and C helices of the cytokine, directly competing with the IL-4Rα interaction.…”

Section: Otheril-4/il-13pathwayantagonistsmentioning

confidence: 99%

Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Bernstein

Shenoy

Chen

et al. 2023

Immunological Reviews

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SummaryThe structurally and functionally related interleukin‐4 (IL‐4) and IL‐13 cytokines play pivotal roles in shaping immune activity. The IL‐4/IL‐13 axis is best known for its critical role in T helper 2 (Th2) cell‐mediated Type 2 inflammation, which protects the host from large multicellular pathogens, such as parasitic helminth worms, and regulates immune responses to allergens. In addition, IL‐4 and IL‐13 stimulate a wide range of innate and adaptive immune cells, as well as non‐hematopoietic cells, to coordinate various functions, including immune regulation, antibody production, and fibrosis. Due to its importance for a broad spectrum of physiological activities, the IL‐4/IL‐13 network has been targeted through a variety of molecular engineering and synthetic biology approaches to modulate immune behavior and develop novel therapeutics. Here, we review ongoing efforts to manipulate the IL‐4/IL‐13 axis, including cytokine engineering strategies, formulation of fusion proteins, antagonist development, cell engineering approaches, and biosensor design. We discuss how these strategies have been employed to dissect IL‐4 and IL‐13 pathways, as well as to discover new immunotherapies targeting allergy, autoimmune diseases, and cancer. Looking ahead, emerging bioengineering tools promise to continue advancing fundamental understanding of IL‐4/IL‐13 biology and enabling researchers to exploit these insights to develop effective interventions.

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“…Indeed, adiponectin activates two of main seven transmembrane receptors, adiponectin receptor 1 (Adipo-R1) and 2 Adipo-R2; which they detected in almost every tissue, but generally with a different expression ratio and affinity for the adipokine oligomers [10]. Physiologically, adiponectin contributes to the 0.05% of total proteins present in the systemic circulation, with a concentration ranging from 3 to 30 μg/mL, depending on hormonal, inflammatory, pharmacological and dietary factors [11]. Increase adiponectin levels have been linked to an increased risk of developing type 2 diabetes, metabolic syndrome, insulin resistance, hypertension, cardiovascular disease, and different malignancies, including breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Tracking the Levels of Adiponectin and Interleukin-18 for Assessing the Efficiency of Chemotherapy in Suppressing Breast Cancer Progression

Rasha Hasan Jasim,

HazimYahya Saeed

2024

J. K. Chem. Sci.

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Breast cancer is a genetically and clinically heterogeneous disease. Cancerous cells multiplying abnormally in the breast, eventually spreading to the rest of the body if untreated. Breast cancer almost exclusively occurs in women. Cancer is a major public health problem worldwide with millions of new cancer patients diagnosed each year and many deaths resulting from this disease. Worldwide, female breast cancer has now surpassed lung cancer as the most commonly diagnosed cancer. SUBJECTS: Ninety two females were included in the current study, they were classified into three groups, depending on their health status (patients and healthy women) and the type of tumor suffered by the study patients: 32 female patients with cancerous breast tumors before receiving chemotherapy, 30 female patients with benign breast tumors (the pathological control group) and 30 females, who were included as a healthy control group. METHODS: Sandwich-ELISA method was applied to evaluate adiponectin and interleukin-18 concentrations in the sera of the study participants. RESULTS: Assessment of the adiponectin revealed a significant increase in the samples of malignant breast tumors group when compared with those of benign breast tumors (p=0.000) and healthy individuals (p=0.002). Interleukin-18 levels in the malignancy tumor group were significantly lower than their levels in the pathological (p=0.007) as well as healthy (p=0.000) controls groups. This study shows apparent slight decrease of adiponectin concentrations in cancerous patients group after getting approximately three consecutive doses of chemotherapy in comparison with its levels pretreatment, while non-significant difference was noted when comparing interleukin-18 levels after receiving the last dose of chemotherapy with its level before starting treatment. Although the levels of interleukin-18 increased after the end of the recommended course of chemotherapy, it did not rise to the levels of this protein in the healthy control group. The individual efficiency (sensitivity) of the evaluated criteria in the current study for distinguishing between cancerous and benign breast tumors was convergent. While the study recorded the highest specificity (93%) for adiponectin while the lowest specificity (40%) was recorded in interleukin-18. Adiponectin and interleukin-18 were able to distinguish 28 out of 32 breast cancer samples (88%).

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A Small-Molecule Inhibitor to the Cytokine Interleukin-4

Cited by 8 publications

References 45 publications

A New Investigation into the Molecular Mechanism of Andrographolide towards Reducing Cytokine Storm

A New Investigation into the Molecular Mechanism of Andrographolide towards Reducing Cytokine Storm

Engineering the IL‐4/IL‐13 axis for targeted immune modulation

Tracking the Levels of Adiponectin and Interleukin-18 for Assessing the Efficiency of Chemotherapy in Suppressing Breast Cancer Progression

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