Open Biology (Jun 2024)
A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex
- Maya Michon,
- Andreas Müller-Schiffmann,
- Anuradha F. Lingappa,
- Shao Feng Yu,
- Li Du,
- Fred Deiter,
- Sean Broce,
- Suguna Mallesh,
- Jackelyn Crabtree,
- Usha F. Lingappa,
- Amanda Macieik,
- Lisa Müller,
- Philipp Niklas Ostermann,
- Marcel Andrée,
- Ortwin Adams,
- Heiner Schaal,
- Robert J. Hogan,
- Ralph A. Tripp,
- Umesh Appaiah,
- Sanjeev K. Anand,
- Thomas W. Campi,
- Michael J. Ford,
- Jonathan C. Reed,
- Jim Lin,
- Olayemi Akintunde,
- Kiel Copeland,
- Christine Nichols,
- Emma Petrouski,
- Ana R. Moreira,
- I-ting Jiang,
- Nicholas DeYarman,
- Ian Brown,
- Sharon Lau,
- Ilana Segal,
- Danielle Goldsmith,
- Shi Hong,
- Vinod Asundi,
- Erica M. Briggs,
- Ngwe Sin Phyo,
- Markus Froehlich,
- Bruce Onisko,
- Kent Matlack,
- Debendranath Dey,
- Jaisri R. Lingappa,
- Dharma M. Prasad,
- Anatoliy Kitaygorodskyy,
- Dennis Solas,
- Homer Boushey,
- John Greenland,
- Satish Pillai,
- Michael K. Lo,
- Joel M. Montgomery,
- Christina F. Spiropoulou,
- Carsten Korth,
- Suganya Selvarajah,
- Kumar Paulvannan,
- Vishwanath R. Lingappa
Affiliations
- Maya Michon
- Prosetta Biosciences, San Francisco, CA, USA
- Andreas Müller-Schiffmann
- Institute of Neuropathology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Anuradha F. Lingappa
- Prosetta Biosciences, San Francisco, CA, USA
- Shao Feng Yu
- Prosetta Biosciences, San Francisco, CA, USA
- Li Du
- Vitalant Research Institute, San Francisco, CA, 94118-4417 USA
- Fred Deiter
- Veterans Administration Medical Center, San Francisco, CA, USA
- Sean Broce
- Prosetta Biosciences, San Francisco, CA, USA
- Suguna Mallesh
- Prosetta Biosciences, San Francisco, CA, USA
- Jackelyn Crabtree
- University of Georgia, Animal Health Research Center, Athens, GA, 28130 USA
- Usha F. Lingappa
- Prosetta Biosciences, San Francisco, CA, USA
- Amanda Macieik
- Prosetta Biosciences, San Francisco, CA, USA
- Lisa Müller
- Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Philipp Niklas Ostermann
- Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Marcel Andrée
- Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Ortwin Adams
- Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Heiner Schaal
- Institute of Virology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Robert J. Hogan
- Vitalant Research Institute, San Francisco, CA, 94118-4417 USA
- Ralph A. Tripp
- Vitalant Research Institute, San Francisco, CA, 94118-4417 USA
- Umesh Appaiah
- Prosetta Biosciences, San Francisco, CA, USA
- Sanjeev K. Anand
- Santo Biotech, LLC, Pendleton, IN, USA
- Thomas W. Campi
- Santo Biotech, LLC, Pendleton, IN, USA
- Michael J. Ford
- MS Bioworks, Ann Arbor, MI, USA
- Jonathan C. Reed
- Onipro LLC, Kensington, CA, USA
- Jim Lin
- Prosetta Biosciences, San Francisco, CA, USA
- Olayemi Akintunde
- Prosetta Biosciences, San Francisco, CA, USA
- Kiel Copeland
- Prosetta Biosciences, San Francisco, CA, USA
- Christine Nichols
- Prosetta Biosciences, San Francisco, CA, USA
- Emma Petrouski
- Prosetta Biosciences, San Francisco, CA, USA
- Ana R. Moreira
- Prosetta Biosciences, San Francisco, CA, USA
- I-ting Jiang
- Prosetta Biosciences, San Francisco, CA, USA
- Nicholas DeYarman
- Prosetta Biosciences, San Francisco, CA, USA
- Ian Brown
- Prosetta Biosciences, San Francisco, CA, USA
- Sharon Lau
- Prosetta Biosciences, San Francisco, CA, USA
- Ilana Segal
- Prosetta Biosciences, San Francisco, CA, USA
- Danielle Goldsmith
- Prosetta Biosciences, San Francisco, CA, USA
- Shi Hong
- Prosetta Biosciences, San Francisco, CA, USA
- Vinod Asundi
- Prosetta Biosciences, San Francisco, CA, USA
- Erica M. Briggs
- Prosetta Biosciences, San Francisco, CA, USA
- Ngwe Sin Phyo
- Prosetta Biosciences, San Francisco, CA, USA
- Markus Froehlich
- Prosetta Biosciences, San Francisco, CA, USA
- Bruce Onisko
- Onipro LLC, Kensington, CA, USA
- Kent Matlack
- Prosetta Biosciences, San Francisco, CA, USA
- Debendranath Dey
- Prosetta Biosciences, San Francisco, CA, USA
- Jaisri R. Lingappa
- Department of Global Health, University of Washington, Seattle, WA, 98195, USA
- Dharma M. Prasad
- Prosetta Biosciences, San Francisco, CA, USA
- Anatoliy Kitaygorodskyy
- Prosetta Biosciences, San Francisco, CA, USA
- Dennis Solas
- Prosetta Biosciences, San Francisco, CA, USA
- Homer Boushey
- University of California, San Francisco, CA, 94143, USA
- John Greenland
- Veterans Administration Medical Center, San Francisco, CA, USA
- Satish Pillai
- Vitalant Research Institute, San Francisco, CA, 94118-4417 USA
- Michael K. Lo
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA
- Joel M. Montgomery
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA
- Christina F. Spiropoulou
- Viral Special Pathogens Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA
- Carsten Korth
- Institute of Neuropathology, Heinrich Heine University, Düsseldorf, 40225 Germany
- Suganya Selvarajah
- Prosetta Biosciences, San Francisco, CA, USA
- Kumar Paulvannan
- Prosetta Biosciences, San Francisco, CA, USA
- Vishwanath R. Lingappa
- Prosetta Biosciences, San Francisco, CA, USA
- DOI
- https://doi.org/10.1098/rsob.230363
- Journal volume & issue
-
Vol. 14,
no. 6
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.
Keywords
- drug discovery
- host–viral interface
- phenotypic screen
- pan-respiratory antiviral therapeutics
- allosteric modulator
- viral capsid assembly
