Structural and molecular characterization of a small-molecule TNF-α-TNFR1 inhibitor modulating cell death signaling - PubMed
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- #TNF-alpha inhibitor
- #cell death signaling
- #small-molecule drug discovery
- TI-16 is a novel small-molecule inhibitor identified via structure-based virtual screening, disrupting the TNF-α/TNFR1 interaction without affecting TNF-α trimerization.
- It protects fibroblasts from TNF-α-induced apoptosis and necroptosis, while also reducing proinflammatory cytokine release, addressing limitations of current biologics.
- Mechanistic validation involved biophysical and cellular assays, immunoblotting, surface plasmon resonance, and molecular dynamics simulations, confirming selective inhibition.
- TI-16 represents a promising lead for orally available TNF-α-targeted therapies, offering an alternative to monoclonal antibodies with issues like immunogenicity and parenteral delivery.