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Principal Investigator: DAVID BAKER
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $713,861
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
One of the most pressing public health priorities for the COVID-19 pandemic is the development of an effective
and inexpensive therapeutic. The long-term goal of this proposal is to develop such COVID-19 treatments, as
well as the methods needed to rapidly create such molecules as soon as any new pathogen is identified. The
central hypothesis is that computational design can be used to quickly create proteins with potent antiviral activity
and others that suppress “cytokine storms” associated with advanced infection. Such countermeasures, if rapidly
developed and deployed, could save millions of lives during an outbreak until vaccines are developed. The
specific aims are to: 1) overcome current limitations in the discovery and development of protein therapeutics by
creating methods for the de novo design of hyper-stable miniproteins that bind tightly to vulnerable binding sites
on the SARS-CoV-2 Spike glycoprotein, including the receptor binding domain (RBD) of the ACE-2 cellular
receptor and the fusion peptide region; 2) Enhance the avidity of such anti-Spike minibinders through genetic
fusion of multiple copies, or through rational design of higher-order oligomers to create drug compounds that are
less prone to viral mutagenic escape; 3) Apply the same minibinder design pipeline to create cytokine receptor
antagonists of key cytokines IL-6 and IL-1β likely involved in acute respiratory distress syndrome (ADRS)
associated with COVID-19 mortality; 4) Assess the efficacy of antiviral and anti-interleukin minibinders by several
routes of delivery (intravenous, intranasal and subcutaneous) in rodent models of COVID-19 and assess
immunogenicity in order to identify those designs best suited for further preclinical development. As proof of
principle, the first anti-Spike minibinders have already been designed, were found to bind to SARS-CoV-2 Spike
RBD, and were found to neutralize live virus with activities rivaling the most potent known antibodies. This
proposal is innovative because it seeks to apply powerful emerging methods in the computational design of new
protein therapeutics to the COVID-19 pandemic. The proposal is significant because it would be the first example
of computational protein design yielding potent and entirely de novo antiviral and anti-inflammatory therapeutics
for an active pandemic. Ultimately, rapid minibinder design methods have the potential to generate treatments
for future pandemics, as well as for many other common and neglected diseases and conditions.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><ARDS><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Aerosols><Affinity><Animals><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antiinflammatories><Antiinflammatory Agents><Antiviral Agents><Antiviral Drugs><Antivirals><Avidity><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Binding><Binding Sites><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 crisis><COVID-19 death><COVID-19 epidemic><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infection><COVID-19 mortality><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapeutics><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 S protein><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 crisis><COVID19 death><COVID19 epidemic><COVID19 fatality><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 pandemic><COVID19 public health crisis><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapeutics><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Capillary Leak Syndrome><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical Treatment Moab><Co-Stimulator><CoV-2><CoV2><Combining Site><Computing Methodologies><Coronaviridae><Coronavirus><Costimulator><Coupled><Cytokine Receptors><Da Nang Lung><Development><Disease><Disease Outbreaks><Disorder><Drug Compounding><Drug Kinetics><Drug Preparation><Drugs><E coli><E. coli><Early-Stage Clinical Trials><Endothelial Cells><Epidermal Thymocyte Activating Factor><Epithelial Cells><Escherichia coli><Future><Genetic><Glycoproteins><Goals><Golden Hamsters><Golden Syrian Hamsters><HPGF><Hepatocyte-Stimulating Factor><High Affinity Interleukin-2 Receptor><High Performance Computing><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-2><IL-2 Receptors><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL2 Protein><IL2 Receptors><IL6 Protein><Infection><Inflammatory><Inflammatory Response><Influenza HA><Influenza Hemagglutinin><Interleukin 1beta><Interleukin 2><Interleukin 2 Precursor><Interleukin 2 Receptor><Interleukin II><Interleukin-1 beta><Interleukin-1β><Interleukin-2><Interleukin-6><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Interleukins><Intracellular Communication and Signaling><Intravenous><K-18><K-18 conjugate><K18><K18 combination><Lead><Life><Lymphocyte Mitogenic Factor><MGI-2><Medication><Mesocricetus auratus><Methods><Mice><Mice Mammals><Mission><Mitogenic Factor><Modeling><Modern Man><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Myeloid Differentiation-Inducing Protein><NIH><National Institutes of Health><Nebulizer><Organ failure><Outbreaks><Outcome><Pb element><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasmacytoma Growth Factor><Preinterleukin 1 Beta><Protein Engineering><Proteins><Protocol><Protocols documentation><Public Health><Reactive Site><Receptor Protein><Research><Rodent Model><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 pandemic><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><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 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 therapeutics><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><Sepsis><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 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 infection><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 coronavirus 2 therapeutics><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Social Behavior><Specificity><Stiff lung><Syrian Hamsters><System><Systemic Capillary Leak Syndrome><T cell growth factor><T-Cell Growth Factor><T-Cell Growth Factor Receptors><T-Cell Stimulating Factor><TCGF Receptors><Testing><Therapeutic><Thymocyte Stimulating Factor><United States National Institutes of Health><Viral><Viral Diseases><Virus><Virus Diseases><Work><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><antagonist><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral therapeutic><anti-virals><antiinflammatory><antiviral compound><antiviral efficacy><antiviral medication><antiviral therapeutic><biological signal transduction><blood infection><bloodstream infection><clinical development><computational methodology><computational methods><computer based method><computer methods><computing method><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapeutics><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 mortality><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><cost><cytokine><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disability><drug/agent><emerging pathogen><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><flu HA><flu hemagglutinin><genetic protein engineering><hCoV19><heavy metal Pb><heavy metal lead><high-end computing><immunogenicity><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><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><inhibitor><innovate><innovation><innovative><interferon beta 2><mAbs><mimetics><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nCoV2><native protein drug><neglect><new drug treatments><new drugs><new pathogen><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pathogen><novel therapeutics><novel therapy><pandemic><pandemic disease><parallel computation><parallel computer><parallel computing><pathogen><pathogen genome><pathogenome><pharmaceutical protein><phase I protocol><pre-clinical development><preclinical development><prophylactic><protein design><protein drug agent><protein-based drug><public health priorities><rational design><receptor><receptor binding><receptor bound><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><small molecule><sociobehavior><sociobehavioral><subcutaneous><subdermal><therapeutic protein><therapeutically effective><therapeutics against COVID-19><therapeutics against COVID19><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><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><vaccine development><viral infection><virus infection><virus-induced disease><wet lung>