A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein
| Autor: | Jinhong Chang, Xuexiang Zhang, Shuo Wu, Andrea Cuconati, Yanming Du, Ju-Tao Guo, Justin G. Julander, John L. Kulp, Timothy M. Block, Julia Ma, Fang Guo |
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| Přispěvatelé: | American Society for Microbiology |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Viral protein viruses 030106 microbiology Immunology Yellow fever vaccine Dairy Science Biology medicine.disease_cause Microbiology Virus 03 medical and health sciences Virology Vaccines and Antiviral Agents medicine Mutation Attenuated vaccine Yellow fever medicine.disease Yellow Fever Virus Infection 030104 developmental biology Animal Sciences Insect Science Viral load medicine.drug |
| Zdroj: | Journal of Virology Animal, Dairy, and Veterinary Science Faculty Publications |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.01253-16 |
| Popis: | Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past 2 decades, which highlights the pressing need for antiviral therapeutics. In a high-throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV-infected cultures with 2 μM BDAA reduced the virion production by greater than 2 logs, the compound was not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug-resistant viruses revealed that replacement of the proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine, or alanine conferred YFV with resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, replacement of P219 with glycine conferred BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 amino acid is localized at the endoplasmic reticulum lumen side of the fifth putative transmembrane domain of NS4B, and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed an important role and the structural basis for the NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs, and attenuated virus infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever. IMPORTANCE Yellow fever is an acute viral hemorrhagic disease which threatens approximately 1 billion people living in tropical areas of Africa and Latin America. Although a highly effective yellow fever vaccine has been available for more than 7 decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to 60,000 deaths. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we identified a benzodiazepine compound that selectively inhibits YFV by targeting the viral NS4B protein. To our knowledge, this is the first report demonstrating in vivo safety and antiviral efficacy of a YFV NS4B inhibitor in an animal model. We have thus reached a critical milestone toward the development of specific antiviral therapeutics for clinical management of yellow fever. |
| Databáze: | OpenAIRE |
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