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Principal Investigator: Michael S Kay
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2020
Award: $429,481
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The 21st century has seen the emergence of multiple lethal human coronaviruses (SARS-CoV, MERS-CoV,
and now SARS-CoV-2). There is an urgent need for therapeutic options to combat the current and inevitable
future SARS-like pandemics. Coronaviruses infect cells using a conserved entry mechanism shared by viruses
across multiple families (including HIV, Ebola, and influenza) in which two regions of the trimeric viral spike
protein (HR1 and HR2) collapse to form a highly stable six-helix bundle structure that forces the viral and
cellular membranes together, inducing membrane fusion. Inhibitor binding to HR1 blocks six-helix bundle
formation and stops viral entry, preventing infection. Our lab specializes in mirror-image phage display (MIPD),
an innovative approach to identify novel synthetic protease-resistant D-peptide drug candidates, with a special
focus on the inhibition of viral entry (with our HIV-1 drug, CPT31, set to begin clinical trials). D-peptides
(peptides composed of mirror-image D-amino acids) cannot be digested by proteases in the body and,
therefore, possess significant therapeutic advantages including extended half-life, lower dosing, reduced
immunogenicity (not digested for MHC presentation), and durability in protease-rich environments such as the
respiratory tract. To address the current health crisis, we are expediting our drug discovery process to identify
D-peptide entry inhibitors that target the conserved HR1 of SARS-related coronaviruses. We have designed,
synthesized, and characterized our HR1 mimic drug targets and are using them in MIPD to identify D-peptide
inhibitors of 6-helix bundle formation and viral entry.
In this proposal, we will chemically synthesize the D-peptides identified by MIPD and characterize their
target affinity (using surface plasmon resonance) and antiviral activity against SARS-CoV and SARS-CoV-2
pseudoviruses. Promising D-peptides will be affinity-matured using a second round of MIPD to optimize
potency. Using our custom-designed PEG scaffold (the backbone of CPT31), we will trimerize the highest
affinity D-peptide candidates to improve avidity for the trimeric spike target and attach a membrane-localizing
group, such as cholesterol, that will enrich the D-peptide at the cellular site of viral entry and improve in vivo
half-life. These leading D-peptides will be tested against authentic virus (in collaboration with USU's Institute
for Antiviral Research). Our objective is to have one D-peptide candidate with ≤100 nM in vitro EC90 against
SARS-CoV-2 and SARS and a good therapeutic index (EC50/CC50 >100) to advance to in vivo PK and efficacy
studies, using USU's hamster model of SARS-CoV-2 infection. At the end of the grant period, we expect to
have one D-peptide lead with demonstrated in vivo animal efficacy, poised for IND-enabling preclinical studies
and development as a SARS-related coronavirus treatment and/or preventative.
Terms: <2019 novel coronavirus><2019-nCoV><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Affinity><Amino Acids><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Avidity><Binding><Bioassay><Biochemical><Biologic Assays><Biological Assay><Blood Plasma><COVID-19 epidemic><COVID-19 pandemic><COVID19 epidemic><COVID19 pandemic><Cell Body><Cells><Cellular Membrane><Chemicals><Cholesterol><Clinical Research><Clinical Study><Clinical Trials><Collaborations><Complex><Consensus><Consensus Sequence><Coronaviridae><Coronavirus><Cricetinae><Custom><Disease Outbreaks><Dose><Drug Targeting><Drugs><Ebola><Environment><Esteroproteases><Family><Funding><Future><Goals><Grant><Grippe><HCoV><HIV><HIV-1><HIV-I><HIV1><Half-Life><Hamsters><Hamsters Mammals><Health><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Image><In Vitro><Infection><Infection prevention><Influenza><Institutes><Isoleucine><LAV-HTLV-III><Lead><Libraries><Lung><Lung Respiratory System><Lymphadenopathy-Associated Virus><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Medication><Membrane><Membrane Fusion><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Modification><Molecular Interaction><Mutate><Outbreaks><Parents><Pb element><Peptidases><Peptide Hydrolases><Peptide Synthesis><Peptides><Phage Display><Pharmaceutic Preparations><Pharmaceutical Preparations><Phase><Plant Embryos><Plant Zygotes><Plasma><Plasma Serum><Position><Positioning Attribute><Pre-clinical Drug Testing/Development><Preclinical Drug Development><Preclinical Drug Testing/Development><Prevent infection><Process><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Pulmonary Body System><Pulmonary Organ System><Research><Resistance><Resolution><Respiratory System><Respiratory Tracts><Respiratory tract structure><Reticuloendothelial System, Serum, Plasma><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Seeds><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Single Crystal Diffraction><Site><Solid><Spinal Column><Spine><Structure><Surface><Surface Plasmon Resonance><Technology><Testing><Therapeutic><Therapeutic Index><Universities><Utah><Vaccines><Vertebral column><Viral><Virus><Virus-HIV><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><aminoacid><animal efficacy><anti-viral agents><anti-viral drugs><anti-virals><backbone><clinical care><combat><corona virus><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><design><designing><drug candidate><drug discovery><drug/agent><efficacy study><flu infection><heavy metal Pb><heavy metal lead><human CoV><human corona virus><human coronavirus><imaging><immunogenicity><improved><in vivo><in vivo evaluation><in vivo testing><influenza infection><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><membrane structure><novel><pandemic><pandemic disease><peptide drug><pre-clinical development><pre-clinical drug development><pre-clinical study><preclinical development><preclinical study><preference><pulmonary><resistant><scaffold><scaffolding><screening><seed><severe acute respiratory syndrome-CoV><therapeutic peptide><virus envelope>