Project One: Small-Molecule Inhibitors of Flavivirus Entry

Dengue virus and other flaviviruses including West Nile virus, tick-borne encephalitis virus, and Yellow Fever virus, are widespread, mosquito- or tick-borne human pathogens. About 40% of the world's population lives in areas with substantial risk of dengue transmission, and as many as 100 million people may be infected annually, experiencing dengue fever and potentially lethal severe dengue. Development of a vaccine effective against all four dengue serotypes has been difficult because infection with one of the four serotypes does not lead to protective immunity against any of the... Read more

Project Two: Small Molecule Inhibitors of Ebola Virus Infection

Ebola virus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality, and lack of effective vaccine or anti-viral therapy have created a high level of public concern about EboV.

EboV are enveloped viruses that enter cells by attachment of the envelope glycoprotein GP to cell surface lectins and uptake into cytoplasmic vesicles by macropinocytosis16,17. Virus-containing vesicles fuse with endosomes, and virus particles are transported to lysosomes... Read more

Project Three: Discovery of New Cellular Targets for Small-Molecule Inhibition of Enveloped Virus Entry

To determine whether cellular proteins are effective targets for small molecule inhibitors of enveloped RNA virus entry, this project will define the cellular factors required for the entry of a large panel of viruses selected from the families Alphaviridae (Chikungunya, Eastern equine encephalitis), Arenaviridae (Lassa, Machupo, Lujo), Bunyaviridae (Rift Valley fever, La Crosse) , Coronaviridae (SARS, human coronavirus Erasmus Medical Center), Filoviridae (Ebola, Marburg) , and Rhabdoviridae (rabies, Australian bat lyssavirus, Bas Congo). These families include some of the most lethal... Read more

Project Four: Identify Where Small-Molecule Inhibitors and Host Proteins Subvert Entry of Enveloped Viruses

Understanding the pathway(s) that a virus follows during infectious penetration will greatly facilitate the development of useful entry inhibitors. We outline plans to use contemporary tools of live-cell and single- molecule imaging to provide quantitative descriptions of the invasion of mammalian cells by viral pathogens, including analysis of molecular mechanisms of membrane fusion. We will use an advanced live-cell, spinning-disk confocal fluorescence imaging configuration, with very sensitive optics and optimized illumination, for long time-course studies of viral entry and penetration... Read more