NAK Inhibitors for Combating Dengue, Ebola, COVID-19, and Other Emerging Viral Infections
Abstract
A major threat to military Service Members and global health is posed by emerging viruses, the FY20 PRMRP Topic Area this project addresses, such as dengue (DENV), severe acute respiratory syndrome-coronovirus-2 (SARS-CoV-2), Ebola (EBOV), and chikungunya (CHIKV). There are currently no approved drugs or vaccines available against the majority of emerging viruses. DENV 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. CHIKV is another 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. Coronavirus outbreaks present a military and global threat, as demonstrated by the current COVID-19 outbreak, which has infected a large number of troops across military installations globally. Furthermore, military readiness of our country is greatly impacted by the presence of this virus in our military training facilities. EBOV and other related filoviruses cause outbreaks with increasing frequency in equatorial Africa, and continue to present grave threats to humans. US troops are at continuous risk of acquiring filovirus infections while on duty. 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 as well as preparedness for future outbreaks with newly emerging viruses. The typical 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. While remdesivir and a few related drugs suppress replication of multiple viruses in cultured cells and animals, they have shown only mild to moderate clinical utility. Approaches that target cellular functions required for replication of multiple viruses can provide effective broad-spectrum solutions. For the past decade, our laboratory has been studying the role of cellular proteins in the trafficking of viruses inside human cells and as targets for broad-spectrum antivirals. We have provided a proof of concept for the potential feasibility of the host-targeted broad-spectrum antiviral approach by demonstrating that the inhibition of three cellular proteins from the NAK family, AAK1/BIKE and GAK, by approved anticancer drugs protects mice from dengue and Ebola viruses with a high barrier to resistance. While this approach is now advancing into clinical studies for dengue infections, we wish to develop novel, chemically distinct, “next generation” NAK inhibitors that by avoiding activity on other cellular proteins have improved safety and utility. This project’s goal is to advance the development of selective NAK inhibitors for treating multiple emerging viral infections. Our former PRMRP-funded project generated two very promising, chemically distinct lead GAK inhibitors and a lead AAK1/BIKE inhibitor that show improved antiviral activity against DENV, EBOV, and CHIKV. Excitingly, our recent data indicate that our compounds suppress SARS-CoV-2 replication to undetectable levels at non-toxic concentrations. Our main objective is to improve various properties of these compounds and advance them to preclinical animal models. 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, in unique human “organ on a chip” models, and in well-characterized small animal (rodent) models. Lastly, we will conduct studies to define dosing regimens, the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110456
Entities
People
- Shirit Einav
Organizations
- Stanford University
- United States Army