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Modulating IL-1β-induced pro-atherogenic endothelial responses through drug repurposing.

Kundan Solanki1, Sk Rameej Raja1, Sunanda Samanta1

  • 1Mehta Family School of Biosciences and Biomedical Engineering (MFS-BSBE), Indian Institute of Technology Indore (IITI), Indore, Madhya Pradesh, 453552, India.

Inflammopharmacology
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PubMed
Summary
This summary is machine-generated.

Radotinib and lomitapide effectively inhibit Interleukin-1β (IL-1β) signaling, protecting endothelial function. These repurposed drugs offer promising, accessible alternatives to current biologic therapies for vascular inflammation.

Keywords:
AtherosclerosisEndothelial dysfunctionIL-1βMacrophagesNOS1Vascular inflammation

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Area of Science:

  • Cardiovascular Science
  • Pharmacology
  • Molecular Biology

Background:

  • Interleukin-1β (IL-1β) drives vascular inflammation and endothelial dysfunction, contributing to atherosclerosis.
  • Current biologic therapies targeting IL-1β are effective but costly and invasive.
  • Accessible small-molecule inhibitors are needed to modulate IL-1β signaling and preserve endothelial function.

Purpose of the Study:

  • Identify repurposed small-molecule drugs targeting IL-1β signaling.
  • Evaluate their efficacy in protecting endothelial function.

Main Methods:

  • Integrated computational (virtual screening, docking, simulations) and experimental approaches.
  • In vitro evaluation using endothelial cell models (HUVEC, EA.hy.926).
  • Functional assays including TEER, VE-cadherin immunofluorescence, and cell viability.

Main Results:

  • Radotinib and lomitapide showed high binding affinity to IL-1R1 in silico.
  • Both compounds reduced IL-1β-induced endothelial dysfunction in vitro.
  • They restored barrier integrity, improved TEER, and maintained VE-cadherin expression with low cytotoxicity.

Conclusions:

  • Radotinib and lomitapide are promising repurposed inhibitors of IL-1β signaling.
  • These compounds preserve endothelial integrity and reduce inflammation.
  • They represent potential cost-effective, orally available alternatives to biologic therapies.