Novel Benzoxazole Inhibitor of Dengue Virus Replication That Targets the NS3 Helicase
| Autor: | Eric Stavale, Janet M. Leeds, Guang Yang, Stone Melialani A C L, Chris Harver, Douglas W. Grosenbach, Christine Schneider, Dongcheng Dai, Kevin F. Jones, Jessica M. Page, Kristin A. Wineinger, Candace Lovejoy, Robert Jordan, Kara B. Cardwell, Chelsea M. Byrd, Dennis E. Hruby, Aklile Berhanu, Kathleen P. Fuller, Shanthakumar R. Tyavanagimatt |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
viruses
Viremia Dengue virus Biology Viral Nonstructural Proteins medicine.disease_cause Virus Replication Antiviral Agents Virus Dengue fever Cell Line Dengue Mice Dogs Drug Resistance Viral medicine Animals Humans Pharmacology (medical) Pathogen Vero Cells Pharmacology Benzoxazoles virus diseases biochemical phenomena metabolism and nutrition Dengue Virus medicine.disease Virology Infectious Diseases Viral replication Vero cell Viral load RNA Helicases HeLa Cells |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| Popis: | Dengue virus (DENV) is the predominant mosquito-borne viral pathogen that infects humans with an estimated 50 to 100 million infections per year worldwide. Over the past 50 years, the incidence of dengue disease has increased dramatically and the virus is now endemic in more than 100 countries. Moreover, multiple serotypes of DENV are now found in the same geographic region, increasing the likelihood of more severe forms of disease. Despite extensive research, there are still no approved vaccines or therapeutics commercially available to treat DENV infection. Here we report the results of a high-throughput screen of a chemical compound library using a whole-virus assay that identified a novel small-molecule inhibitor of DENV, ST-610, that potently and selectively inhibits all four serotypes of DENV replication in vitro . Sequence analysis of drug-resistant virus isolates has identified a single point mutation, A263T, in the NS3 helicase domain that confers resistance to this compound. ST-610 inhibits DENV NS3 helicase RNA unwinding activity in a molecular-beacon-based helicase assay but does not inhibit nucleoside triphosphatase activity based on a malachite green ATPase assay. ST-610 is nonmutagenic, is well tolerated (nontoxic) in mice, and has shown efficacy in a sublethal murine model of DENV infection with the ability to significantly reduce viremia and viral load compared to vehicle controls. |
| Databáze: | OpenAIRE |
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