A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex.

Autor: Michon M; Prosetta Biosciences, San Francisco, CA, USA., Müller-Schiffmann A; Institute of Neuropathology, Heinrich Heine University, Düsseldorf, 40225 Germany., Lingappa AF; Prosetta Biosciences, San Francisco, CA, USA., Yu SF; Prosetta Biosciences, San Francisco, CA, USA., Du L; Vitalant Research Institute, San Francisco, CA, 94118-4417 USA., Deiter F; Veterans Administration Medical Center, San Francisco, CA, USA., Broce S; Prosetta Biosciences, San Francisco, CA, USA., Mallesh S; Prosetta Biosciences, San Francisco, CA, USA., Crabtree J; University of Georgia, Animal Health Research Center, Athens, GA, 28130 USA., Lingappa UF; Prosetta Biosciences, San Francisco, CA, USA., Macieik A; Prosetta Biosciences, San Francisco, CA, USA., Müller L; Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany., Ostermann PN; Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany., Andrée M; Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany., Adams O; Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany., Schaal H; Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany., Hogan RJ; Vitalant Research Institute, San Francisco, CA, 94118-4417 USA., Tripp RA; Vitalant Research Institute, San Francisco, CA, 94118-4417 USA., Appaiah U; Prosetta Biosciences, San Francisco, CA, USA., Anand SK; Santo Biotech, LLC, Pendleton, IN, USA., Campi TW; Santo Biotech, LLC, Pendleton, IN, USA., Ford MJ; MS Bioworks, Ann Arbor, MI, USA., Reed JC; Onipro LLC, Kensington, CA, USA., Lin J; Prosetta Biosciences, San Francisco, CA, USA., Akintunde O; Prosetta Biosciences, San Francisco, CA, USA., Copeland K; Prosetta Biosciences, San Francisco, CA, USA., Nichols C; Prosetta Biosciences, San Francisco, CA, USA., Petrouski E; Prosetta Biosciences, San Francisco, CA, USA., Moreira AR; Prosetta Biosciences, San Francisco, CA, USA., Jiang IT; Prosetta Biosciences, San Francisco, CA, USA., DeYarman N; Prosetta Biosciences, San Francisco, CA, USA., Brown I; Prosetta Biosciences, San Francisco, CA, USA., Lau S; Prosetta Biosciences, San Francisco, CA, USA., Segal I; Prosetta Biosciences, San Francisco, CA, USA., Goldsmith D; Prosetta Biosciences, San Francisco, CA, USA., Hong S; Prosetta Biosciences, San Francisco, CA, USA., Asundi V; Prosetta Biosciences, San Francisco, CA, USA., Briggs EM; Prosetta Biosciences, San Francisco, CA, USA., Phyo NS; Prosetta Biosciences, San Francisco, CA, USA., Froehlich M; Prosetta Biosciences, San Francisco, CA, USA., Onisko B; Onipro LLC, Kensington, CA, USA., Matlack K; Prosetta Biosciences, San Francisco, CA, USA., Dey D; Prosetta Biosciences, San Francisco, CA, USA., Lingappa JR; Department of Global Health, University of Washington, Seattle, WA, 98195, USA., Prasad DM; Prosetta Biosciences, San Francisco, CA, USA., Kitaygorodskyy A; Prosetta Biosciences, San Francisco, CA, USA., Solas D; Prosetta Biosciences, San Francisco, CA, USA., Boushey H; University of California, San Francisco, CA, 94143, USA., Greenland J; Veterans Administration Medical Center, San Francisco, CA, USA.; University of California, San Francisco, CA, 94143, USA., Pillai S; Vitalant Research Institute, San Francisco, CA, 94118-4417 USA.; University of California, San Francisco, CA, 94143, USA., Lo MK; Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA., Montgomery JM; Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA., Spiropoulou CF; Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA., Korth C; Institute of Neuropathology, Heinrich Heine University, Düsseldorf, 40225 Germany., Selvarajah S; Prosetta Biosciences, San Francisco, CA, USA., Paulvannan K; Prosetta Biosciences, San Francisco, CA, USA., Lingappa VR; Prosetta Biosciences, San Francisco, CA, USA.; University of California, San Francisco, CA, 94143, USA.
Jazyk: angličtina
Zdroj: Open biology [Open Biol] 2024 Jun; Vol. 14 (6), pp. 230363. Date of Electronic Publication: 2024 Jun 19.
DOI: 10.1098/rsob.230363
Abstrakt: 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.
Databáze: MEDLINE