Genome wide mapping of host proteome: pan alphavirus proteome interactions for discovery of broad spectrum countermeasures
Abstract
New World alphaviruses pose an important threat to the warfighter and the lack of FDA approved countermeasures for the treatment of alphavirus exposure is a critical unmet need in the biodefense community. We propose to identify in a genome-wide capacity, protein: protein interactions between the alphavirus proteins and host proteins using proteomics approaches. The short term output of this effort will be a pan-alphavirus: host protein interactome map and the long term benefits of this study will be the delineation of multiple host-based, broad spectrum targets to support therapeutic development. Our approach is based on the rationale that viral proteins rely on dynamic interactions with host proteins to complete important aspects of their life cycle which makes these host proteins ideal targets for intervention. We propose to identify host proteins and several inhibitor candidates, including FDA approved inhibitors that have broad spectrum roles in influencing alphavirus infection. We have successfully demonstrated using proteomic strategies, that the nonstructural protein 3 (nsP3) of Venezuelan Equine Encephalitis Virus (VEEV) interacts with an array of host proteins including kinases, RNA helicases and translational initiation components. We propose to extend this research to encompass alphavirus nonstructural and structural proteins to create a protein interaction map of pan alphavirus: host proteome interactions and identify host protein targets that are common to New World alphaviruses. We will provide proof of concept (POC) demonstration of target relevance to viral multiplication using small molecule inhibitors in cell culture and mouse models of infection.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- HDTRA11810040
Entities
People
- Aarthi Narayanan
Organizations
- Defense Threat Reduction Agency
- George Mason University