Research Project
9592816
ABSTRACT This is a proposal to develop a highly selective and potent antiviral benzodiazepine compound against yellow fever virus (YFV) as a therapeutic agent for treatment of yellow fever and understand its antiviral mechanism. Yellow fever is an acute viral hemorrhagic disease which threatens approximately one billion people living in tropical areas of Africa, Central and South America. Although a highly effective yellow fever vaccine has been available for more than seven 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, which outnumber the estimated death toll of global dengue virus infection. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we discovered an acetic acid benzodiazepine (BDAA) compound that potently inhibited YFV replication in both mammalian and insect cells by targeting the viral non-structural 4B (NS4B) protein. We have already demonstrated in YFV-infected hamsters that oral administration of BDAA significantly protected the animals from death, reduced viral load by greater than 2 logs and attenuated viral infection-induced liver injury and body weight loss. Building on these encouraging preclinical studies, we propose in this project to optimize the lead compound to obtain benzodiazepine derivatives with improved solubility and reduced plasma protein binding ability to achieve improved in vivo antiviral efficacy and safety profile. Meanwhile, we will continue our efforts toward understanding the molecular mechanism by which BDAA and its derivatives inhibit YFV replication. Specifically, impacts of the compound on NS4B protein metabolism, integrity and function of viral RNA replication complex as well as YFV interaction with host cellular innate immune response will be investigated. At the completion of this project, we will nominate an optimized benzodiazepine derivative as well as backup compounds for further preclinical/clinical development. In addition to knowing how the compound inhibits YFV replication, our studies proposed in this project should also enrich our knowledge on the function of NS4B protein in YFV replication and evasion of host innate immunity.
