Glycopolymer Inhibitors of Heparan Sulfate Proteoglycan Binding Pathogens
Project Number5SC3GM119521-08
Former Number5SC3GM119521-04
Contact PI/Project LeaderMCREYNOLDS, KATHERINE D
Awardee OrganizationCALIFORNIA STATE UNIVERSITY SACRAMENTO
Description
Abstract Text
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.
Public Health Relevance Statement
PROJECT NARRATIVE:
This project is focused on the development of two different types of carbohydrate-containing polymers as
potential broad-spectrum anti-viral agents. If successful, these molecules could be used to shorten the length of
time someone is symptomatic, and/or decrease the mortality rate associated with the viral infections, particularly
those caused by pandemic-causing viruses like SARS-CoV-2 and HIV-1.
No Sub Projects information available for 5SC3GM119521-08
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