Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses

• Published in: Antimicrobial agents and chemotherapy 2016-03, Vol.60 (3), p.1615-1626
• Main Authors: Zuo, Jun, Kye, Steve, Quinn, Kevin K, Cooper, Paige, Damoiseaux, Robert, Krogstad, Paul
• Format: Article
• Language: English
• Subjects: Antiviral Agents; Antiviral Agents - pharmacology; Carrier Proteins; Carrier Proteins - antagonists & inhibitors; Cell Line, Tumor; Coxsackievirus Infections; Coxsackievirus Infections - drug therapy; Enterovirus; Enterovirus - drug effects; HeLa Cells; High-Throughput Screening Assays; Humans; Microbial Sensitivity Tests; Small Molecule Libraries; Small Molecule Libraries - pharmacology; Viral Nonstructural Proteins; Viral Nonstructural Proteins - antagonists & inhibitors; Virus Replication; Virus Replication - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02646-15

Antiviral drugs do not currently exist for the treatment of enterovirus infections, which are often severe and potentially life-threatening. We conducted high-throughput molecular screening and identified a structurally diverse set of compounds that inhibit the replication of coxsackievirus B3, a commonly encountered enterovirus. These compounds did not interfere with the function of the viral internal ribosome entry site or with the activity of the viral proteases, but they did drastically reduce the synthesis of viral RNA and viral proteins in infected cells. Sequence analysis of compound-resistant mutants suggests that the viral 2C protein is targeted by most of these compounds. These compounds demonstrated antiviral activity against a panel of the most commonly encountered enteroviruses and thus represent potential leads for the development of broad-spectrum anti-enteroviral drugs.