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Antiviral compounds displaying several remarkable features have been identified by a uniquely enabling drug screen and advanced through validation in two animal models, and in human primary bronchial epithelial cells grown to an air-liquid interface (ALI) and infected with SARS-CoV-2 (Brazil). Activity is observed in the nanomolar range in mammalian cells in vitro against the six viral families causing most human respiratory viral disease, irrespective of strain, including SARS-CoV-2 delta variant. A substantial barrier to development of viral resistance is demonstrated for influenza (FLUV). The drug target is an allosteric site on a novel host multi-protein complex (MPC) formed transiently, in an energy-dependent fashion, and composed of proteins implicated in viral lifecycles and innate immunity. The composition of this host MPC is modified in viral family-specific ways by FLUV and CoV, and substantially restored to the uninfected state with drug treatment. SQSTM1/p62, a key regulator of the autophagy pathway of innate immunity is i) found in the target MPC from uninfected cells, ii) lost upon infection, and iii) restored by drug treatment of infected cells, as assessed by drug resin affinity chromatography. A small subset of 14-3-3 is identified as the host protein to which the drug is bound. Advanced compounds with good oral bioavailability, half-life, lung exposure, and safety are approaching criteria for a Target Product Profile. We propose these novel drug targets to comprise a previously unappreciated molecular basis for homeostasis that is modified by viruses to facilitate their propagation and is restored by treatment with the therapeutic compounds presented. This discovery has transformative implications for treating respiratory viral-related disease, applicable to everything from COVID-19, seasonal influenza, common ‘winter viruses’ (respiratory syncytial virus, parainfluenza virus, rhinovirus, etc.), emerging respiratory viruses, and prevention of virus-induced asthma/COPD exacerbations. Treating respiratory viral disease with these host-targeted pan-respiratory viral family active compounds early, upon onset of symptoms of viral upper respiratory infection, irrespective of cause, should protect against progression to lower respiratory tract or systemic infection, the hallmarks of serious illness.