AI Article Synopsis

  • Researchers developed a new small molecule antiviral called PAV-431 that was discovered through a unique screening method targeting viral protein assembly.
  • This compound has shown effectiveness against various respiratory viruses in laboratory studies and in animal models, including coronaviruses and paramyxoviruses.
  • PAV-431 works by selectively targeting a modified protein complex involved in the viral life cycle, providing a potential new approach for treating respiratory viral infections without harming the host.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285769PMC
http://dx.doi.org/10.1098/rsob.230363DOI Listing

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