Ebola and Marburg are enveloped viruses of the family Filoviridae. As category A pathogens that cause fatal hemorrhagic fevers, they are considered to be significant biodefense threats. Currently there are no approved antiviral agents or vaccines to combat these devastating pathogens.
Recent successes in combating HIV infections support the concept of inhibiting enveloped virus entry by blocking virus binding to or fusion with host cells. The long-term objective of this project is to develop small molecule inhibitors and/or therapeutic antibodies that block binding or fusion of Ebola and Marburg viruses with host cells. Our work to date supports the following model for Ebola virus entry: following binding to an as of yet unidentified receptor(s), Ebola virus is endocytosed and delivered to an endosome. There, cathepsins B and L cleave the receptor binding subunit (GP1) of the Ebola virus glycoprotein (GP) into a 19kDa intermediate that confers enhanced binding and infection. Thus, 19kDa GP1 defines a receptor-binding domain (RBD) of GP. A final cathepsin L dependent activity triggers fusion and hence virus entry into the cell cytoplasm. The major goal of this proposal is to explore blockade of Ebola and Marburg virus binding to host cells as a means to prevent infection and therefore to ameliorate disease sequelae. To attain this goal we will address the following Specific Aims:
1. identify host cell receptor(s) for Ebola and Marburg viruses;
2. pan for and characterize mAbs that bind to the Ebola and Marburg virus RBDs; and
3. develop and employ a high throughput screen for small molecules that block receptor binding.
The project will involve state of the art genomic, proteomic, molecular virological, and high throughput screening approaches. The project has a very high degree of health relatedness. Given the extremely high morbidity and mortality rates of filovirus infections, there is a pressing need for a collection of agents to combat filovirus infections in both pre- and post-exposure situations, for example for health care, animal care, and laboratory research workers as well as for local populations at large during an outbreak.
Judith White