{Reference Type}: Journal Article
{Title}: A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex.
{Author}: Michon M;Müller-Schiffmann A;Lingappa AF;Yu SF;Du L;Deiter F;Broce S;Mallesh S;Crabtree J;Lingappa UF;Macieik A;Müller L;Ostermann PN;Andrée M;Adams O;Schaal H;Hogan RJ;Tripp RA;Appaiah U;Anand SK;Campi TW;Ford MJ;Reed JC;Lin J;Akintunde O;Copeland K;Nichols C;Petrouski E;Moreira AR;Jiang IT;DeYarman N;Brown I;Lau S;Segal I;Goldsmith D;Hong S;Asundi V;Briggs EM;Phyo NS;Froehlich M;Onisko B;Matlack K;Dey D;Lingappa JR;Prasad DM;Kitaygorodskyy A;Solas D;Boushey H;Greenland J;Pillai S;Lo MK;Montgomery JM;Spiropoulou CF;Korth C;Selvarajah S;Paulvannan K;Lingappa VR;
{Journal}: Open Biol
{Volume}: 14
{Issue}: 6
{Year}: 2024 Jun
{Factor}: 7.124
{DOI}: 10.1098/rsob.230363
{Abstract}: We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.