Selective AAK1 and GAK Inhibitors for Combating Dengue and Other Emerging Viral Infections
Abstract
A major threat to military Service members and global health is posed by emerging viruses, such as dengue, chikungunya, and Ebola. There are currently no approved drugs or vaccines available against these viruses. Dengue virus, the Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area this project addresses, has substantially weakened US military operations since the Spanish-American War. With the global increase in dengue incidence and severity, it has become even a greater threat to military troops. Chikungunya, another emerging viral infection that this project addresses, is a major concern for the US military, due to the global distribution of this virus and its capability to rapidly incapacitate personnel and cause a debilitating chronic joint inflammation. Ebola virus and other related filoviruses cause outbreaks with increasing frequency in equatorial Africa, and they continue to present grave threats to humans. The establishment of AFRICOM means that US troops are at continuous risk of acquiring filovirus infections while on duty. US troops were deployed to Liberia during the recent devastating Ebola virus disease outbreak, placing them directly in harm s way. There is also a great concern that each of these viruses may be used as a biological weapon. There is thus a critical need for effective broad-spectrum anti-infectives capable of conferring protection against these and other multiple emerging viral threats. The current antiviral approach is based on targeting individual viruses. Such a "one drug, one threat" approach is both inefficient and impractical for providing protection against the wide array of viral threats. We recently discovered that two host proteins, named AAK1 and GAK, are absolutely critical for the lifecycle of multiple viruses. We also discovered inhibitors of these proteins, including two already approved anticancer drugs, sunitinib and erlotinib, with potent activity against multiple emerging viruses. While this approach is now advancing into clinical studies for dengue and Ebola infections, we wish to develop novel, chemically distinct, "next-generation" AAK1 and GAK inhibitors that by avoiding activity on other cellular proteins (beyond AAK1 and GAK) have improved safety and utility. This project s goal is to optimize novel inhibitors that selectively inhibit AAK1 and/or GAK and that have already demonstrated great promise against dengue virus, and advance their development towards a near-clinical stage product. This approach would also protect against multiple other biothreat agents, including chikungunya virus and ebolavirus. To achieve this goal, we will optimize our inhibitors to ensure they can achieve adequate blood and tissue levels over an adequate period of time. We will study the therapeutic potential of these optimized compounds by examining their effect against multiple emerging viruses both in tissue culture models and in well-characterized small animal (rodents) models. We will also de-risk the clinical development of these compounds by studying their safety in animal models. Lastly, we will conduct studies to define dosing regimens, thereby assisting the design of future clinical studies with these compounds. The short-term impact is that this project will deliver an antiviral compound(s) with demonstrated efficacy against dengue, which can also provide protection against numerous other emerging viruses. It is thus intended to fill a large gap in our military and public health capabilities, with potential implications for biodefense. A therapeutic with broad-spectrum potential could be deployed with troops, providing a means to rapidly treat these devastating illnesses in the field. The long-term impact is that such a therapeutic could be administered even before the viral threat has been accurately diagnosed, thus increasing chances of protection. Our project diverts from the prevailing "one drug, one threat" treatment paradigm, thereby me
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610692
Entities
People
- John M Dye
Organizations
- Geneva Foundation
- United States Army