Coronaviruses severely threaten livestock production, exacting a considerable economic toll. Pathogens such as the porcine epidemic diarrhea virus (PEDV) have resulted in the deaths of millions of pigs in the US alone between 2013-5, while other coronaviruses are continuously emerging. Hence the desired solution should be able to combat both current and future coronaviruses. While vaccines can often be used as a prevention strategy, cost-effective and effective therapeutics also represent a critical part of a response platform to both endemic and epidemic infectious diseases. Our research proposal aims to provide such a platform for animal coronavirus diseases, based on the recent advances that have been made in coronavirus studies due to the tremendous focus of the research community on SARS-CoV-2 (the etiological agent of COVID-19). In particular, we will exploit a specific vulnerability in coronaviruses – ion channels. As a family, channels have proven to be highly attractive targets for pharmaceutical inhibition. Recent studies on SARS-CoV-2 have shown that channel blockers can effectively curb viral infectivity in cellulo and in vivo, providing proof-of-concept to our proposal.

Our research program involves a synergistic combination of efforts between the Israeli and US groups. The Israeli group will employ its recently-developed bacteria-based assays to identify and characterize channels in agriculturally important coronaviruses such as PEDV, BCoV, IBV, and PDCoV. The fact that analyses are conducted in bacteria enables rapid pivoting to new viral strains and threats.

The Israeli group will then proceed to utilize the aforementioned assays (purposefully designed for screening) to search for inhibitors of the channels it identified. The Israeli group has used this procedure very recently to identify channels in SARS-CoV-2, find inhibitors thereof, and demonstrate that these blockers can potentially hinder viral infectivity in cellulo. The US groups will subsequently analyze the efficacy of any of the leads the Israeli group identified in cellulo using the long-standing expertise and resources of the Whittaker and Diel labs, which have studied both human and animal coronaviruses for almost 20 years. Compounds that are capable of impacting viral infectivity in a tissue culture system represent attractive drug candidates for future translation into animal studies. Our drug development cycle will also take into account viral resistance towards any compound we identify. In brief, the Israeli group will again use a bacteria-based assay in which the viral channel is essential to bacterial growth. In such an instance, a resistance mutation can readily be detected upon randomly mutagenizing the viral channel and identifying bacteria that can grow in the presence of the blocker.

In conclusion, our research program offers a platform that can be applied to any coronavirus-yielding inhibitors to curb infectivity. It was recently shown to work on SARS-CoV-2 and, as such, represents an attractive approach to increase our arsenal against agriculturally important coronaviruses.