Selective AAK1 and GAK Inhibitors for Combating Dengue and Other Emerging Viral Infections
Abstract
We discovered an Achilles' heel of unrelated viruses: a requirement for AP2-associated protein kinase 1 (AAK1) and cyclin Gassociated kinase (GAK), host kinases that regulate clathrin adaptor proteins-mediated pathways. Our data point to AAK1 and GAK as "master regulators" of viral infection and attractive targets for broad-spectrum antivirals. We discovered that approved anticancer drugs that target these kinases; sunitinib and erlotinib, potently inhibit replication of multiple viruses invitro and reduce mortality in mice infected with DENV and EBOV. This approach is now being advanced to the clinic for both of these indications. Nevertheless, while sunitinib and erlotinib are quite potent inhibitors of AAK1 or GAK, respectively, they are not selective and are therefore associated with toxicity resulting from inhibition of other host cellkinases. The goals of this proposal are to: optimize novel, chemically distinct, selective lead AAK1 and GAK inhibitors targeting validated virus-host interactions and already demonstrating great promise against DENV, and advance their development to a near-IND stage. This approach would also protect against biothreat agents from eight viral families, including EBOV and CHIKV.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2017
- Accession Number
- AD1050996
Entities
People
- Jennifer M. Brannan
- John M Dye
Organizations
- Geneva Foundation