A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex
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Published:2024-06
Issue:6
Volume:14
Page:
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ISSN:2046-2441
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Container-title:Open Biology
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language:en
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Short-container-title:Open Biol.
Author:
Michon Maya1, Müller-Schiffmann Andreas2, Lingappa Anuradha F.1, Yu Shao Feng1, Du Li3, Deiter Fred4, Broce Sean1, Mallesh Suguna1, Crabtree Jackelyn5, Lingappa Usha F.1, Macieik Amanda1, Müller Lisa6, Ostermann Philipp Niklas6, Andrée Marcel6, Adams Ortwin6, Schaal Heiner6, Hogan Robert J.3, Tripp Ralph A.3, Appaiah Umesh1, Anand Sanjeev K.7, Campi Thomas W.7, Ford Michael J.8, Reed Jonathan C.9, Lin Jim1, Akintunde Olayemi1, Copeland Kiel1, Nichols Christine1, Petrouski Emma1, Moreira Ana R.1, Jiang I-ting1, DeYarman Nicholas1, Brown Ian1, Lau Sharon1, Segal Ilana1, Goldsmith Danielle1, Hong Shi1, Asundi Vinod1, Briggs Erica M.1, Phyo Ngwe Sin1, Froehlich Markus1, Onisko Bruce9, Matlack Kent1, Dey Debendranath1, Lingappa Jaisri R.10, Prasad Dharma M.1, Kitaygorodskyy Anatoliy1, Solas Dennis1, Boushey Homer11, Greenland John411, Pillai Satish311, Lo Michael K.12, Montgomery Joel M.12, Spiropoulou Christina F.12, Korth Carsten2, Selvarajah Suganya1, Paulvannan Kumar1, Lingappa Vishwanath R.111ORCID
Affiliation:
1. Prosetta Biosciences, San Francisco, CA, USA 2. Institute of Neuropathology, Heinrich Heine University, Düsseldorf, 40225 Germany 3. Vitalant Research Institute, San Francisco, CA, 94118-4417 USA 4. Veterans Administration Medical Center, San Francisco, CA, USA 5. University of Georgia, Animal Health Research Center, Athens, GA, 28130 USA 6. Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany 7. Santo Biotech, LLC, Pendleton, IN, USA 8. MS Bioworks, Ann Arbor, MI, USA 9. Onipro LLC, Kensington, CA, USA 10. Department of Global Health, University of Washington, Seattle, WA, 98195, USA 11. University of California, San Francisco, CA, 94143, USA 12. Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA
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.
Funder
Prosetta Biosciences
Publisher
The Royal Society
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