Document text
Principal Investigator: Ariel Jade Kuhn
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $73,828
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of coronavirus
disease (COVID-19), has spurred an unprecedented global pandemic. Infection surges necessitate new
therapeutic agents that are effective against a rapidly changing virus. Antivirals that inhibit viral entry into host
cells have proven effective against other viruses with similar mechanisms of pathogenesis.
The long-term objective of this highly collaborative proposed research is to develop potent peptides
inhibitors of SARS-CoV-2 infection that operate by blocking structural rearrangements of the spike protein
required for viral entry into host cells. For SARS-CoV-2 infection to occur, the viral surface spike (S) protein, a
homotrimer, rearranges to form an energetically favored postfusion state. In this postfusion conformation, two
helical domains, the N-terminal (HRN) and C-terminal (HRC) heptad repeats, associate to form a 6-helix bundle
(6HB). Peptides derived from the HRC can inhibit formation of the 6HB, and thus SARS-CoV-2 infection.
However, conventional peptides, composed entirely of α-amino acid residues, are highly susceptible to
proteolytic degradation, which necessitates frequent and high dosing. The Gellman lab, in collaboration with
virologists Prof. Anne Moscona and Prof. Matteo Porotto at Columbia University, has demonstrated that site-
selective incorporation of backbone modifications, in combination with cholesterol conjugation, can decrease
proteolytic sensitivity while maintaining high antiviral potency. Our team recently found that such lipopeptides
can inhibit SARS-CoV-2 infection in biological assays and animal models, and that these inhibitors are effective
against SARS-CoV-2 variants, SARS-CoV-1 and MERS. Building on this foundation, my proposed project seeks
to develop lipopeptides containing backbone modifications that display high antiviral potency and resist
proteolysis. Aim 1 will produce potent inhibitors of SARS-CoV-2 (and other coronaviruses) that contain backbone
modifications and resist proteolysis. Aim 2 will evaluate the stability of 6HB formation between inhibitor
candidates and the native SARS-CoV-2 HRN. Aim 3 will elucidate critical structural interactions between the
HRC mimics and the native HRN.
My hypothesis is that site-selective incorporation of backbone modifications into HRC-based designs will
increase both antiviral activity and half-life in vivo, improving therapeutic efficacy. The proposed research, which
will be conducted under the guidance of Prof. Sam Gellman at the University of Wisconsin, will provide me with
experience in macromolecular X-ray crystallography, molecular design, protein engineering & expression, and
virology. Through structure-guided engineering and sophisticated and multi-pronged assay
implementation, these efforts could generate effective pan-variant therapeutics for COVID-19.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Amino Acid Substitution><Amino Acids><Animal Model><Animal Models and Related Studies><Anti-viral Agents><Assay><Bioassay><Bioavailability><Biodistribution><Biological Assay><Biological Availability><C-terminal><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapeutics><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CV-19><Causality><Cell Body><Cell membrane><Cells><Cessation of life><Chemicals><Cholesterol><Circular Dichroism><CoV disease><CoV-2><CoV2><Collaborations><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Crystallization><Crystallographies><Crystallography><Cytoplasmic Membrane><Data><Death><Development><Dose><Drug Kinetics><Economics><Engineering><Esteroproteases><Etiology><Exhibits><Fluorescence Polarization><Foundations><Goals><HIV><HPIV3><Half-Life><Hemadsorption Virus 1><Human Immunodeficiency Viruses><Human Parainfluenza Virus 3><Hybrids><In Vitro><Infection><Investigators><LAV-HTLV-III><Learning><Length><Lymphadenopathy-Associated Virus><MERS><MERS coronavirus disease><MERS-CoV disease><Mediating><Membrane Fusion><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modification><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><N-terminal><NH2-terminal><Para-Influenza Virus Type 3><Pathogenesis><Peptidases><Peptide Hydrolases><Peptides><Pharmacokinetics><Physiologic Availability><Plasma Membrane><Position><Positioning Attribute><Predisposition><Productivity><Property><Prophylactic treatment><Prophylaxis><Protease Gene><Proteases><Protein Cleavage><Protein Engineering><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><Research><Research Personnel><Researchers><Resistance><Resolution><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapeutics><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><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><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute 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 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 therapeutics><Severe acute respiratory syndrome related corona virus 2><Side><Single Crystal Diffraction><Site><Spinal Column><Spine><Structure><Surface><Surface Proteins><Susceptibility><Techniques><Therapeutic Agents><Treatment Efficacy><Universities><Vaccines><Variant><Variation><Vertebral column><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virus><Virus Diseases><Virus Inhibitors><Virus-HIV><Vulnerable Populations><Wisconsin><Work><Wuhan coronavirus><X Ray Crystallographies><X ray diffraction><X ray diffraction analysis><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><Xray diffraction><aminoacid><analog><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><backbone><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><block viral entry><career><causation><conformation><conformational><conformational state><conformationally><conformations><corona virus><corona virus disease><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapeutics><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><design><designing><developmental><disease causation><economic><experience><genetic protein engineering><hCoV19><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibit viral entry><inhibitor><insight><interdisciplinary approach><intervention efficacy><mimicry><model of animal><multidisciplinary approach><nCoV2><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pandemic><pandemic disease><parainfluenza virus type 3><plasmalemma><protein design><protein expression><resistant><resolutions><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><severe acute respiratory syndrome-CoV><spike proteins on SARS-CoV-2><therapeutic efficacy><therapeutics against COVID-19><therapeutics against SARS-CoV-2><therapeutics against SARS-coronavirus-2><therapeutics against Severe acute respiratory syndrome coronavirus 2><therapeutics against coronavirus disease 2019><therapeutics for novel coronavirus><therapy efficacy><viral entry blocker><viral entry inhibitor><viral infection><viral inhibitor><virology><virus infection><virus-induced disease><vulnerable group><vulnerable individual><vulnerable people>