Repurposing of Pan-ErbB Inhibitors to Protect from Coronaviral Infection, Inflammation, and Lung Injury
Abstract
FY21 Topic Areas: There is an urgent need for more effective approaches to prevent the acute and long-term lung complications associated with COVID-19 and ideally also provide readiness for future outbreaks with coronaviruses and other emerging viruses. By focusing on advancing the repurposing of approved drugs designed to not only suppress replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other emerging viruses but also reduce inflammation and lung injury, this project addresses two FY21 Topic Areas: (1) Emerging Viral Diseases; (2) Respiratory Health. The Unmet Clinical Need: Coronavirus outbreaks present a major 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. While effective vaccines are currently available against SARS-CoV-2 infection, the continuous emergence of new viral variants and limited access to vaccines in various parts of the world, continue to pose challenges, and underscore the urgent need for effective therapeutic countermeasures. To date, the reported clinical benefit in reducing acute and chronic complications and mortality rates of COVID-19 with various antiviral drugs has been limited. Additionally, most drugs that suppress SARS-CoV-2 infection do not directly suppress inflammation and tissue injury, thus requiring combination with anti-inflammatory agents (e.g., steroids) for COVID-19 therapy. Other emerging viruses including filoviruses (e.g., Ebola virus), flaviviruses (e.g., dengue virus) and alphaviruses (e.g., Venezuelan equine encephalitis virus) cause outbreaks with increasing frequency and continue to present grave threats to humans. U.S. troops are at continuous risk of acquiring these infections while on duty. There is also a great concern that 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. Rationale: 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. Since the therapeutic potential of this drug combination is less effective for SARS-CoV-2 infection, in this proposal, we focus on independent kinase inhibitors targeting different pathways that emerged from our recent work. This project’s main goal is to advance the repurposing of existing compounds with potent activity against members of the epidermal growth factor receptor (ErbB1-4) family of kinases, including lapatinib and ibruitinib, approved oral anticancer drug with a favorable safety profile, and/or several investigational drugs (saptinib, afatinib, tesevatinib). Excitingly, our recent data indicate that these compounds suppress SARS-CoV-2 replication to a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210283
Entities
People
- Shirit Einav
Organizations
- Stanford University
- United States Army