Covalent inhibitors of host cell entry by SARS-CoV-2 for treatment of COVID-19

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Principal Investigator: Matthew  Bogyo
Organization: STANFORD UNIVERSITY
Fiscal Year: 2023
Award: $236,100
Funding agency: National Institute of Allergy and Infectious Diseases

Project Summary
Current strategies to overcome virus outbreaks are focused on development of effective vaccines as well as
novel treatments that can either block infection or prevent mortality from the resulting disease. One of the
strategies that has shown promise is the use of serum from patients who have recovered from infection. This
strategy relies on the presence of high titers of neutralizing antibodies that bind to antigens on the virus and
block uptake into host cells. For the SARS-CoV-2 virus this requires antibodies that bind to regions on the
receptor binding domain (RBD) of the viral ‘spike’ (S) protein and block its interaction with the host receptor,
angiotensin converting enzyme 2 (ACE2). Significant efforts over the past 15 years of studies on related
coronaviruses has produced a detailed picture of the interactions between these two protein domains. These
studies have facilitated strategies to select optimal neutralizing antibodies likely to have the greatest
therapeutic value. While antibodies are effective biological therapies, they suffer from limitations that make
their widespread use for a global pandemic limited. This includes the high cost of production, poor uptake by
oral or localized administration and general incompatibility with long-term storage and stockpiling. Furthermore,
interactions with the target viral proteins are reversible and can be rendered ineffective for antibody
neutralization through single point mutations in virus variants. In this proposal, we outline plans to develop a
phage display screening approach to identify synthetic cyclic peptides that carry a covalent ‘warhead’ to induce
specific and permanent binding to the SARS-CoV-2 S protein at highly conserved and functionally important
residues. This approach will lead to the identification of fully synthetic molecules that irreversibly block key
interactions between the S protein RBD and the host cell receptor, ACE2. Such molecules will possess the
selectivity of antibodies but can be synthesized and handled like small molecule drugs. Furthermore, their
covalent binding mode will lead to prolonged therapeutic effects and reduced ability to induce resistance
causing mutations in the S protein.

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Immunosorbent Assay><Esteroproteases><F element><Fluorides><Fluorine><Future><Genetic Alteration><Genetic Change><Genetic defect><Goals><Health><Human><Infection><Knowledge><Libraries><Ligand Binding><Mainland China><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Medication><Methods><Modern Man><Modification><Molecular Interaction><Mutation><Oral><Outbreaks><Patients><Peptidases><Peptide Domain><Peptide Hydrolases><Phage Display><Phages><Pharmaceutic Preparations><Pharmaceutical Preparations><Point Mutation><Production><Protease Gene><Proteases><Protein Domains><Proteinases><Proteins><Proteolytic Enzymes><Proteomics><Reaction><Receptor Cell><Receptor Protein><Resistance><Resolution><S element><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapeutics><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 therapeutics><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serum><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-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 infection><Severe acute respiratory syndrome coronavirus 2 spike 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