Glycopolymer Inhibitors of Heparan Sulfate Proteoglycan Binding Pathogens

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PROJECT SUMMARY/ABSTRACT The current COVID-19 pandemic has resulted in millions of infections and over 2 million deaths worldwide since SARS-CoV-2 emerged in Wuhan, China in December of 2019. This pandemic has revealed a significant treatment gap in the ability to minimize the morbidity and mortality of those infected through the use of anti-viral drugs. Currently only remdesivir has been granted Emergency Use Authorization (EUA) by the FDA, but requires IV administration for 5-10 days at high cost, and has not demonstrated a significant reduction in the length of illness or death rate for severely ill patients. Even with two vaccines with EUA, and more on the horizon, it is likely that the SARS-CoV-2 virus and COVID-19 will persist and may become endemic. As such, vulnerable individuals will still get infected and may die if new anti-viral drugs are not developed soon. The primary aim of this proposal is to synthesize two different types of branched glycopolymers as potential broad spectrum anti-viral (BSAV) drugs. Our second major aim seeks to assess the glycopolymers for anti-viral activity against SARS-CoV-2 and HIV-1, both of which are responsible for current, significant pandemics affecting millions of people around the world. SARS-CoV-2 and HIV-1, along with many other viruses, share the ability to hijack cell surface heparan sulfate proteoglycans (HSPGs) as receptors in the early-stage binding/infection process. This is accomplished through electrostatic interactions between the viral surface glycoproteins, Spike (S, SARS-CoV-2) and gp120 (HIV-1). The glycopolymers will be designed to have polyanionic charges complementary to the polybasic regions of S and gp120. Using the two different classes of glycopolymers will allow for a more rapid assessment of which specific architectural features are most critical to yield the desired anti-viral effect. This will be accomplished using a rapid iterative design build test process where the glycopolymers are built in parallel, then assessed for anti-viral activities using first an ELISA (Enzyme- Linked Immunosorbent Assay) to evaluate viral protein binding and provide a “go/no go” decision. If positive binding is observed, then higher level bioassays will be used to assess quantitative binding (Kd) information, live cell anti-viral assays to provide IC50 (inhibitory concentration for 50% reduction in infection) values, and cytotoxicity evaluation. Computational methods will also be used to ascertain the most critical structural features present in the binding interactions (location, number of contact points, etc.). Evaluation of the comprehensive biological/structural results will inform further iterations of glycopolymer designs. Successful completion of this project has the potential to yield a new class of BSAV. This is crucial for fighting not only the current pandemics caused by both SARS-CoV-2 and HIV-1, but could also provide relief for future viruses not yet emerged.