A basic research pipeline for discovery and early preclinical development of host-targeted antiviral strategies to combat encephalitic alphaviruses
Abstract
Major threats to the warfighter are posed by Venezuelan (VEEV), Eastern (EEEV) and Western (WEEV) equine encephalitis viruses, for which no FDA approved drugs or vaccines are available. Our overall goal is to establish a basic research pipeline for: i) identification of host targets critical for encephalitic alphaviruses; ii) discovery and optimization of relevant inhibitors, and; iii) proof of concept (POC) demonstration of their potential as host-targeted broad-spectrum anti-alphavirals. We discovered an Achilles heel of multiple unrelated viruses, including alphaviruses: a requirement for the host kinases AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK). Combinations of sunitinib and erlotinib; approved anticancer drugs with activity against these kinases, inhibit replication of multiple viruses in vitro and reduce mortality in mice infected with dengue and Ebola viruses. This drug combination is being advanced into clinical trials for these indications. We have also been developing chemically distinct, selective inhibitors of AAK1 and GAK as a next generation antiviral strategy. Our recent data indicate that these inhibitors have potent activity against alphaviruses in vitro and high probability to effectively cross the blood brain barrier (BBB). We hypothesize that selective, potent inhibitors of AAK1 and/or GAK represent attractive, safe candidates for broad-spectrum anti-alphavirals. We also hypothesize that integrating advanced genome-wide screens with innovative bioinformatics approaches can effectively identify common host factors critical for alphavirus infection, as well as existing compounds targeting these host factors with broad-spectrum antiviral activity, thus diversifying our pipeline’s portfolio. We will use an interdisciplinary approach to test these hypotheses, thereby providing insight into the interplay between alphaviruses and the host and nominating candidate inhibitors at a pre-IND stage for further development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- HDTRA11810039
Entities
People
- Shirit Einav
Organizations
- Defense Threat Reduction Agency
- Stanford University