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Principal Investigator: KATHERINE D MCREYNOLDS
Organization: CALIFORNIA STATE UNIVERSITY SACRAMENTO
Fiscal Year: 2024
Award: $106,500
Funding agency: National Institute of General Medical Sciences
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Affinity><Alkynes><Anti-viral Agents><Architecture><Assay><Azides><Binding><Binding Proteins><Bioassay><Biological><Biological Assay><Businesses><COVID assay><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 assay><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 years><COVID19 assay><COVID19 virus><CV-19><Carbohydrates><Cell Body><Cell Line><Cell Surface Glycoproteins><Cell Surface Receptors><Cell surface><CellLine><Cells><Cessation of life><Charge><China><CoV-2><CoV2><Computing Methodologies><Coronavirus Infectious Disease 2019><Death><Death Rate><Dendrimers><Dendritic Compounds><Dendrons><Development><Disease><Disorder><ELISA><Electrons><Electrostatics><Energy Transfer><Engineering / Architecture><Enzyme-Linked Immunosorbent Assay><Evaluation><FDA EUA><FDA Emergency Use Authorization><Food and Drug Administration EUA><Food and Drug Administration Emergency Use Authorization><Future><GS-5734><Goals><Grant><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-I><HIV1><HSPG><HTLV-III gp120><Heparan Sulfate Proteoglycan><Herd Immunity><History><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Hydroxyimino Compounds><In Vitro><Infection><LAV-HTLV-III><Length><Life><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Location><Luciferase Immunologic><Luciferases><Lymphadenopathy-Associated Virus><Lytotoxicity><Mainland China><Measures><Membrane Glycoproteins><Methods><Molecular Dynamics Simulation><Molecular Interaction><Morbidity><Morbidity - disease rate><Negative Beta Particle><Negatrons><Outcome><Oximes><PET><PET Scan><PET imaging><PETSCAN><PETT><Patients><Persons><Polymers><Porphyrins><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Process><Protein Binding><Proteins><Proteoheparan Sulfate><Rad.-PET><Receptor Protein><Recording of previous events><S element><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 assay><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Strains Cell Lines><Sulfate><Sulfur><Surface Glycoproteins><Time><Vaccines><Veklury><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Gene Products><Viral Gene Proteins><Viral Physiology><Viral Proteins><Virus><Virus Diseases><Virus-HIV><Vulnerable Populations><Work><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><biologic><bound protein><computational methodology><computational methods><computer based method><computer methods><computing method><copolymer><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 assay><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease assay><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><cost><cross reactivity><cultured cell line><current pandemic><cycloaddition><cytotoxicity><design><design,build,test><designing><developmental><disease duration><disease length><emergency use authorization><enzyme linked immunoassay><fighting><future pandemic><gp120><gp120 ENV Glycoprotein><gp120(HIV)><hCoV19><histories><illness length><improved><inhibitor><innovate><innovation><innovative><iterative design><molecular dynamics><monomer><mortality><mortality rate><mortality ratio><nCoV2><next pandemic><novel><pandemic><pandemic disease><pathogen><polymer><polymeric><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><present pandemic><prevent><preventing><receptor><remdesivir><school closing><school closure><screening><screenings><severe acute respiratory syndrome coronavirus 2 assay><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><spike proteins on SARS-CoV-2><sugar><viral infection><virus infection><virus protein><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people>