Protocatechualdehyde demonstrates broad-spectrum antiviral activity against EV-A71 and CVB3 with dual neuroprotective and cardioprotective effects in preclinical models.
Viral mutations persistently challenge vaccine development, whereas the multi-target nature of natural products offers promise for broad-spectrum antivirals. Modern bioinformatics enables systematic virtual screening of such agents. This study focuses on enteroviruses, which are particularly concerning due to their ability to cause severe infections in immunocompromised individuals, especially children, with the aim of developing effective broad-spectrum therapeutics. To predict and validate broad-spectrum anti-enteroviral agents through in silico screening and systems pharmacology, followed by experimental assessment of antiviral efficacy in vitro and in vivo . First, systems pharmacology was utilized to predict the broad-spectrum potential of protocatechualdehyde, a natural compound with documented anti-inflammatory/antioxidant properties. Subsequently, in vitro antiviral activity and cytotoxicity were evaluated in Vero cells. Finally, a neonatal mouse model mimicking pediatric infection was used to assess in vivo efficacy. Protocatechualdehyde exhibited potent in vitro activity against EV-A71 (EC 50 = 1.45 μM) and CVB3 (EC 50 = 2.41 μM) with high selectivity indices (SI), indicating low cytotoxicity. Critically, protocatechualdehyde significantly improved survival and alleviated clinical symptoms in lethal infection models. Histopathology confirmed its organ-specific protection: protocatechualdehyde preserved neuronal integrity in vulnerable brain regions (hippocampus, thalamus) of EV-A71 infection and reduced cardiomyocyte shrinkage, nuclear condensation, and eosinophilic infiltration in myocardium of CVB3 infection. Protocatechualdehyde is a promising broad-spectrum antiviral against phylogenetically distinct enteroviruses (EV-A71/CVB3), demonstrating dual neuroprotective and cardioprotective effects. Its efficacy in pediatric-relevant models underscores translational potential for severe enteroviral infections.
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