{"title":"Pterostilbene Exhibits Broad-Spectrum Antiviral Activity by Targeting the Enterovirus Capsid, Inactivating Viral Particles, Blocking Viral Binding, and Protecting Mice From Lethal EV-A71 Challenge.","authors":"Kuan-Ting Chuang, Siao-Cian Pan, Bor-Luen Chiang, Shih-Hsun Chen, Min-Hsiung Pan, Yu-Li Chen, Cheng-Sheng Lin, Chun-Kai Pan, Jing-Yi Lin, Yu-Li Lin","doi":"10.1002/ptr.8496","DOIUrl":null,"url":null,"abstract":"<p><p>Human enteroviruses (EVs) are a major public health issue worldwide owing to their potential to cause respiratory illnesses, hand-foot-and-mouth disease, and severe neurological complications. Currently, no effective drugs or multivalent vaccines are available. Pterostilbene (Pte), a naturally occurring compound found in blueberries and other plants, is a type of stilbene with a similar structure to resveratrol. Pterostilbene exerts antioxidant, anti-inflammatory, and anticancer properties. However, few studies have explored its antiviral activity. This study aimed to investigate the anti-enteroviral effect and mechanisms of Pte against EV-A71 and EV-D68. Cytotoxicity and antiviral assays were performed to assess the safety of Pte to cells and its antiviral effects against enteroviruses. Viral attachment, inactivation assays, cellular receptor binding, western blotting, time-of-addition and time-of-removal assays, particle stability thermal release assay, and molecular docking were performed to elucidate the antiviral mechanisms of Pte. Additionally, we validated the antiviral effects of Pte using in vivo experiments. Among the stilbenes examined, Pte exerted a broad-spectrum inhibitory effect on various enteroviruses, including EV-A71, EV-D68, and coxsackieviruses at 40 μM, without cytotoxicity. Mechanistically, Pte significantly inhibited enteroviral attachment, inactivated viral particles, blocked viral binding to its receptors, and increased virion stability. Molecular docking analysis revealed that Pte occupied a hydrophobic pocket in viral protein 1, indicating a strong binding affinity and acting as an efficient inhibitor. Notably, sequence alignment of multiple enteroviruses indicated that the Pte-interacting residues in VP1 were highly conserved. In vivo studies demonstrated that oral administration of Pte significantly alleviated infection symptoms and reduced mortality in hSCARB2 transgenic mice. Pte possesses potential application as a broad-efficacy antiviral drug against enteroviral infections.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.1000,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178775/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytotherapy Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ptr.8496","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
Human enteroviruses (EVs) are a major public health issue worldwide owing to their potential to cause respiratory illnesses, hand-foot-and-mouth disease, and severe neurological complications. Currently, no effective drugs or multivalent vaccines are available. Pterostilbene (Pte), a naturally occurring compound found in blueberries and other plants, is a type of stilbene with a similar structure to resveratrol. Pterostilbene exerts antioxidant, anti-inflammatory, and anticancer properties. However, few studies have explored its antiviral activity. This study aimed to investigate the anti-enteroviral effect and mechanisms of Pte against EV-A71 and EV-D68. Cytotoxicity and antiviral assays were performed to assess the safety of Pte to cells and its antiviral effects against enteroviruses. Viral attachment, inactivation assays, cellular receptor binding, western blotting, time-of-addition and time-of-removal assays, particle stability thermal release assay, and molecular docking were performed to elucidate the antiviral mechanisms of Pte. Additionally, we validated the antiviral effects of Pte using in vivo experiments. Among the stilbenes examined, Pte exerted a broad-spectrum inhibitory effect on various enteroviruses, including EV-A71, EV-D68, and coxsackieviruses at 40 μM, without cytotoxicity. Mechanistically, Pte significantly inhibited enteroviral attachment, inactivated viral particles, blocked viral binding to its receptors, and increased virion stability. Molecular docking analysis revealed that Pte occupied a hydrophobic pocket in viral protein 1, indicating a strong binding affinity and acting as an efficient inhibitor. Notably, sequence alignment of multiple enteroviruses indicated that the Pte-interacting residues in VP1 were highly conserved. In vivo studies demonstrated that oral administration of Pte significantly alleviated infection symptoms and reduced mortality in hSCARB2 transgenic mice. Pte possesses potential application as a broad-efficacy antiviral drug against enteroviral infections.
期刊介绍:
Phytotherapy Research is an internationally recognized pharmacological journal that serves as a trailblazing resource for biochemists, pharmacologists, and toxicologists. We strive to disseminate groundbreaking research on medicinal plants, pushing the boundaries of knowledge and understanding in this field.
Our primary focus areas encompass pharmacology, toxicology, and the clinical applications of herbs and natural products in medicine. We actively encourage submissions on the effects of commonly consumed food ingredients and standardized plant extracts. We welcome a range of contributions including original research papers, review articles, and letters.
By providing a platform for the latest developments and discoveries in phytotherapy, we aim to support the advancement of scientific knowledge and contribute to the improvement of modern medicine.