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Principal Investigator: Anne Moscona
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2023
Award: $718,692
Funding agency: National Institute of Allergy and Infectious Diseases
No vaccines or treatments for SARS-CoV-2 are yet available. A simple prophylactic antiviral strategy would
protect naïve individuals from infection now. In the future, when vaccines should be available, a prophylactic
antiviral will be essential for individuals who do not mount a suitable immune response. Antivirals that target
viral entry into the host cell have been proven effective against a wide range of viral diseases. The entry/fusion
process for CoV (including SARS-CoV-2) is mediated by the viral envelope glycoprotein (S). Concerted action
by the receptor-binding domain and the fusion domain is required for fusion. Upon viral attachment (and uptake
in certain cases), large-scale conformational rearrangements occur in the fusion domain, driven by formation of
a structure that couples protein refolding directly to membrane fusion. The formation of this structure can be
targeted by fusion inhibitory peptides (C-terminal heptad repeat or HRC peptides) that prevent proper
apposition of the HRC and HRN domains in S. We have found that conjugation of a lipid to an inhibitory
peptide directs the peptide to cell membranes and increases antiviral efficacy. Analogous lipo-peptides prevent
infection by several viruses (measles, Nipah, parainfluenza, influenza), and can be administered via the
airway. Treatment is effective for some of these even several days after infection. In addition, we have shown
that modifying the backbone of an HRC peptide via periodic replacement of α-amino acid residues with β-
amino acid residues generates α/β-peptides that retain antiviral potency (toward HIV or parainfluenza) but are
highly resistant to proteolysis. We recently generated an HRC lipopeptide that is effective against both SARS-
CoV2 and MERS live viruses in vitro, blocks spread of SARS-CoV2 in human airway tissue, and inhibits
transmission of SARS-CoV-2 between ferrets in direct contact. Here we propose to combine the lipid
conjugation and backbone-modification strategies to generate potent inhibitors of SARS-CoV2 infection that
display a long half-life in vivo.
1. Optimize the antiviral potency and bioavailability of SARS-CoV-2 HRC peptide fusion inhibitors via
rational molecular engineering. Antiviral efficacy of α/β-lipopeptide candidates will be measured in
quantitative in vitro assays, in authentic virus infection, and in a human airway model.
2. Evaluate the protection afforded by new backbone-modified α/β-lipopeptide fusion inhibitors against
SARS-CoV-2 infection in hamsters. Analysis of in vivo biodistribution and toxicity of backbone modified S-
CoV-2 α/β-lipopeptide fusion inhibitors and assessment of in vivo potency and resistance mechanisms will lay
the foundation for a safe and effective SARS CoV-2 fusion inhibitor for coronavirus prevention and
therapy.
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><Amino Acids><Animals><Antiviral Agents><Antiviral Drugs><Antiviral resistance><Antiviral resistant><Antivirals><B.1.1.7><Binding><Bioavailability><Biodistribution><Biological Availability><Biophysics><Body Tissues><C-terminal><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 anti-viral><COVID-19 antiviral><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 outbreak><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapy><COVID-19 transmission><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID-19 virus transmission><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 outbreak><COVID19 pandemic><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cell Body><Cell Culture Techniques><Cell fusion><Cell membrane><Cell surface><Cells><Cholesterol><Clinical><CoV-2><CoV2><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Couples><Cricetinae><Cytoplasmic Membrane><Data><Disease><Disorder><Dose><Engineering><Esteroproteases><Evolution><Ferrets><Foundations><Future><Generations><Glycoproteins><Goals><Grippe><HIV><Half-Life><Hamsters><Hamsters Mammals><Host Factor><Host Factor Protein><Human><Human Immunodeficiency Viruses><Immune response><Immunological response><In Vitro><Individual><Infection><Infection prevention><Influenza><Integration Host Factors><LAV-HTLV-III><Lipids><Lymphadenopathy-Associated Virus><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Measles><Measures><Mediating><Membrane><Membrane Fusion><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Modification><Molecular><Molecular Configuration><Molecular 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Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 entry inhibitor><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 outbreak><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><Site><Spinal Column><Spine><Structure><Structure of respiratory epithelium><Susceptibility><Therapeutic><Tissues><Toxic effect><Toxicities><Translating><U.K. variant><UK strain><UK variant><United Kingdom variant><Vaccines><Vertebral column><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus><Virus Diseases><Virus-Cell Interaction><Virus-Cell Membrane Interaction><Virus-HIV><Work><Wuhan coronavirus><airway epithelium><aminoacid><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral resistance><anti-viral resistant><anti-viral therapeutic><anti-virals><antiviral compound><antiviral efficacy><antiviral medication><antiviral therapeutic><backbone><beta CoV><beta coronavirus><betaCoV><betacoronavirus><biophysical foundation><biophysical principles><biophysical sciences><block SARS-CoV-2><block SARS-CoV-2 entry><block severe acute respiratory syndrome coronavirus 2><block severe acute respiratory syndrome coronavirus 2 entry><block viral entry><cell culture><cell 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