Translating Anti-Coronavirus Virucidal Compounds

The current coronavirus (COVID-19) pandemic has highlighted the world's need for effective antivirals. These drugs have to be ready at the start of the pandemic so to stop (best case scenario) or, at least, to slow down the contagion by decreasing the average number of infected people by a single sick patient. We need drugs to buy time for vaccine development. It should be obvious that, for a drug to be ready even before a new virus emerges, it has to be a broad-spectrum one. The PI and co-PI have been working for years to develop such drugs. It is known that the vast majority of respiratory (and sexually transmitted) viruses have attachment ligands that share a common target. They either attach to heparan sulfate proteoglycans (HSPG) or sialic acid (SA). Many compounds that imitate HSPG or SA have been developed over the years. Most of them have shown broad-spectrum activity in vitro and very low toxicity (the paramount example would be heparin). None has been translated into a drug. The key stumbling block lies in the mechanism itself. The virus binds to these compounds (and not to the cell surface) and hence is blocked in its cell-entry process. Binding, though, is a reversible event and, upon dilution (an inevitable event in vivo), the compounds-virus complex disassociates leaving an infective virus to replicate and re-start the infection process. A few years ago, the PI discovered that these compounds can be modified so that, upon binding to the viruses, they exert a local interaction capable of irreversibly damaging the virus. The result is an irreversible interaction because the virus can never regain its infectivity. Two classes of materials have been developed, one capable of mimicking HSPG and the other mimicking SA. In both cases results from ex vivo (on human respiratory tissues) and in vivo (in mice) experiments confirm the efficacy of the compounds. Direct comparison between comparable 'reversible' and 'irreversible' molecules show the superiority of the latter ones in tissues and animals. The key compounds in each of these classes are modified cyclodextrins. Cyclodextrins were chosen because they are naturally occurring sugars commonly used in commercial deodorants or as FDA approved Active Pharmaceutical Ingredients. The scope of this project is that of accelerating substantially the process of taking these molecules towards FDA approval. In order to do this, we propose to (work package 1, WP1) perform glycan arrays and in-depth in vitro study to clarify the interaction mechanism and determine the ideal molecule to inhibit SARS-CoV-2. At the same time, we will (WP2) perform in-depth studies to render the synthesis of the two cyclodextrins compatible with Good Manufacturing Practices (GMP) and render them ready for scale-up production. We will also study (WP3) the stability of the molecules in various storage conditions. Finally, emphasis will be placed in preparing a drug that is not only valuable against SARS-CoV-2 but that has a strong probability to work against the next coronavirus outbreak. In that sense, there will be an effort (WP4) to find conserved targets across the three coronaviruses that have affected humanity in the last twenty years (SARS-CoV, MERS-CoV, and SARS-CoV-2). In this sense, the potential use of a mixture of two or three compounds will be investigated.This project will provide the fundamental science support to other efforts that have been undertaken in the PIs laboratories (pharmacokinetics and toxicity studies, in vivo efficacy studies) that are aimed at rapidly taking these two molecules in Phase I clinical trials. Finally, both the PI and the co-PI are part of Sinergia project in whose framework these molecules were developed. That project is studying the basics of the mechanism of irreversible viral inhibition. This project is complemental to that one as it is designed to lower one of the barriers that exist between the development of an effective molecule and its testing in humans.