Research Project
10156116
Summary Accelerating emergence and re-emergence of a wide array of viral epidemics has been a deadly feature of the 21st century. Potent or even effective therapies are rarely available to combat these diseases, and in general, the world remains unprepared to manage future outbreaks. The most recent outbreak of the Ebola virus resulted in over 11,000 fatalities, more than 20,000 orphans, and economic costs of >$32B (Worldbank), and instilled varying levels of fear in many more. But Ebola is not unique; in 2003 the global economic loss from the SARS virus was ~$40B (WHO). In 2017, there were travel and pregnancy restrictions within the Americas due to the Zika virus and its high correlation with the surge in the incidences of infant microcephaly. Currently, the world is experiencing unprecedented hardship from the life-threatening COVID-19 (SAR2-CoV-2) pandemic, which has already resulted in over 150,000 deaths worldwide, and for which there is no effective therapy or vaccine. Unfortunately, this is neither the first nor the last time the world is expected to be in this plight, unless a broadly acting first-line drug is available for rapid deployment. These outbreaks all resulted from RNA viruses, which remain a major unaddressed disease class. Arenaviruses (e.g. Lassa fever virus and Junin virus), coronaviruses (including SARS-COV-1, SARS-CoV-2, and MERS), and filoviruses (e.g. Ebola and Marburg viruses) are enveloped RNA viruses that cause severe and often fatal human diseases. Despite the global impact and toll on human lives, there are no effective treatment options or FDA-approved vaccines available to combat these devastating infections and they are accordingly classified as NIAID Priority Pathogens and are also on the select agent list of potential bioterrorism threats. This proposal seeks to address this highly significant, unmet clinical need by developing a broad spectrum antiviral agent (BSAA) that targets a fundamental host protein that is commonly subverted by multiple pathogenic virus families but is not essential for the host. In particular, we propose to target the human ER-Golgi intermediate compartment protein 53 kDa protein (ERGIC-53), a mannose-specific lectin that functions as an intracellular cargo receptor to facilitate the anterograde transport of selected cellular glycoprotein ligands in the early exocytic pathway. We have shown that ERGIC-53 is critically required for the propagation of arenaviruses, coronaviruses, and filoviruses. In particular, ERGIC-53 i) associates with the envelope glycoproteins encoded by these viruses as well as orthomyxoviruses and hantaviruses, ii) traffics to sites of virus budding, and iii) is incorporated into viral particles. In the absence of ERGIC-53, viral particles containing the normal array and quantity of viral structural proteins and genome are formed but are no longer infectious. Specifically, virions lacking ERGIC-53 are defective in their ability to attach to host cells. We have mapped the minimal domain within ERGIC-53 that is required for controlling virion infectivity and shown that extracellular targeting of this region potently neutralizes the infectivity of multiple pathogenic RNA viruses. Herein, we have presented strong scientific rationale for targeting ERGIC-53 and proof of concept data that extracellular targeting of ERGIC-53 is an effective antiviral target. Our development plan includes collaborating with Lake Pharma, a company with a proven track record in antibody generation technology. The successful development of potent antiviral monoclonal antibodies targeting ERGIC-53, would be groundbreaking in the treatment of viral outbreaks. Due to its broad spectrum activity and the expected safety of target modulation, ERGIC-53 targeting has the potential to be a first-line strategy against many RNA viruses.
