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A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex by Andreas Müller-Schiffmann; Maya Michon; 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; A. Raquel 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; M. Dharma 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 is a scholarly article available to read on EtoBox.

What is A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex about?

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 virus in multiple cell culture models for all six families of viruses causing most respiratory disease in humans. In animals this chemotype has been demonstrated efficacious for Porcine Epidemic Diarrhea 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 lifecycles 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. 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.

Author

Andreas Müller-Schiffmann; Maya Michon; 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; A. Raquel 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; M. Dharma 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

Publisher

Cold Spring Harbor Laboratory

Published

2023

Language

EN