INP-Guided Network Pharmacology Discloses Multi-Target Therapeutic Strategy Against Cytokine and IgE Storms in the SARS-CoV-2 NB.1.8.1 Variant

The continuous development of SARS-CoV-2 has given rise to the NB1.8.1 variant, which exhibits augmented pathogenicity, immune escape, and drug resistance against traditional therapeutics. The current study investigates a multi-layered systems pharmacology approach for identifying new therapeutic candidates that act on both viral entry and host-mediated inflammatory storms. By combining a seven-layer Intrinsic Network Pharmacology (INP) protocol with Network Pharmacology tools, we dissected the molecular failure network triggered by NB1.8.1, with emphasis on spike protein mutations that increase ACE2 binding, disrupt early interferon responses, and induce extreme cytokine and IgE storms. The HR1 and HR2 domain of the S2 fusion machinery was found to be a key weakness. We identified and confirmed a triterpenoid glycoside, ZINC000014930714, with high-affinity docking into the HR1 groove and strong pseudovirus fusion inhibition. Concurrently, we identified glycyrrhizin, a readily available natural saponin found in licorice, as a suitable surrogate with comparable fusion inhibition. Additional important modulators including camostat as an inhibitor of TMPRSS2, baricitinib targeting JAK and STAT signaling, sulforaphane as a Nrf2 activator, and metformin as an AMPK activator were incorporated into an inhalable nano-liposomal formulation strategy aimed at inhibiting viral propagation and resultant downstream immune storms. Network pharmacology modeling established that the indicated combination closes down several failure nodes in the INP layers. Our research offers a system-wide approach that not only reveals timely antiviral candidates against NB1.8.1 but also provides an adaptive platform for quick transition to emerging SARS-CoV-2 variants.