SARS-CoV-2 Spike protein–Interleukin 6 signal transducer interaction interface (Spike–IL6ST interface)

The SARS-CoV-2 Spike protein–Interleukin 6 signal transducer (IL6ST/gp130) interaction interface refers to the physical contact area between the viral Spike protein and the host cell's gp130 receptor. While ACE2 is the primary receptor for viral entry, research has demonstrated that the Spike protein, specifically the S1 subunit, can bind directly to the D1 domain of gp130 (Gu et al., 2021, Signal Transduction and Targeted Therapy). This interaction triggers the activation of the JAK/STAT3 signaling pathway, which is a major driver of the hyperinflammatory response and cytokine storm observed in severe COVID-19 patients (Wei et al., 2021, Signal Transduction and Targeted Therapy). By bypassing the requirement for systemic IL-6, this direct viral-host interaction provides a mechanism for localized and potent inflammatory signaling in infected tissues. Targeting this interface represents a therapeutic strategy to decouple viral infection from the devastating inflammatory cascades that lead to organ failure. Small molecules like bazedoxifene have been identified as potent inhibitors of this interface, effectively blocking Spike-induced STAT3 phosphorylation and downstream cytokine expression (Wu et al., 2022, Frontiers in Immunology). Because gp130 is a pleiotropic signal transducer shared by multiple cytokines, drug development focusing on this interface must ensure that homeostatic functions, such as tissue repair and hematopoiesis, are not critically compromised. This target is particularly relevant for treating the late-stage inflammatory phase of COVID-19 and potentially other viral infections that utilize similar signaling subversion mechanisms.

Other names

Spike–gp130 interactionSARS-CoV-2 Spike–CD130 interactionS protein–gp130 interfaceSpike–IL6ST PPI

Inhibition of the protein-protein interaction between the SARS-CoV-2 Spike protein and the host Interleukin 6 signal transducer (gp130) to block downstream JAK/STAT3 signaling cascades and reduce pro-inflammatory cytokine production.