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Principal Investigator: James R. Heath
Organization: INSTITUTE FOR SYSTEMS BIOLOGY
Fiscal Year: 2020
Award: $183,000
Funding agency: National Cancer Institute
Project Summary
The pandemic COVID-19 has, as of April 13, 2020, infected nearly 2M individuals worldwide, with over
560,000 U.S. cases and over 22,000 U.S. deaths. There are no FDA approved vaccines or treatments
for COVID-19. This supplemental proposal describes the accelerated development of such a drug,
with potential near-term uses of these early therapeutic candidates for probing the structural-function
relationships between the SARS-CoV-2 spike protein and the human ACE2 receptor protein. This work
builds directly from Project 2 of the NCI-supported U54 NSBCC program. The specific aims of that
project center around the technology of Protein Catalyzed Capture agents (PCCs),1 with a specific
focus on developing technologies for the high-through production of PCCs, as well as an emphasis on
drug-targeting the KRASG12D oncoprotein. A unique aspect of PCCs is that they are, by design,
developed to bind to a specific epitope on a specific protein,2 thus providing an avenue for targeting an
epitope containing a genetic mutation (relevant to oncoproteins),3 or providing an avenue for targeting
epitopes that are broadly conserved, which bears relevance to targeting strategies aimed at the SARS-
CoV-2 coronavirus. That NSBCC-funded project has proceeded well (with progress towards
KRASG12D-specific inhibitors recently attracting additional investments). Further, we have also recently
shown, using other funding, that the platform can be harnessed to selectively target antibiotic resistance
pathogens using a variant of the PCC technology termed antibody-recruiting(AR) PCCs.4 Here we
seek to combine the high-throughput aspect of PCC development that has been supported by the NCI,5
with the pathogen-targeting approach, to develop a series of precisely targeted inhibitors against
SARS-CoV-2. This work has already been moving forward for the past few weeks, and is nearing the
point where animal model work will soon be required.
Terms: <2019 novel coronavirus><2019-nCoV><Administrative Supplement><Affinity><Animal Model><Animal Models and Related Studies><Antibiotic Resistance><Antibodies><Antigenic Determinants><Assay><Bears><Binding><Binding Determinants><Bio-Informatics><Bioassay><Bioinformatics><Biologic Assays><Biological Assay><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Cancer Biology><Cancer Center><Cancers><Cessation of life><Consensus><Coronaviridae><Coronavirus><Coupled><DNA Alteration><DNA Sequence Alteration><DNA mutation><Death><Development><Disease><Disorder><Drug Targeting><Drugs><Engineering><Ensure><Epitopes><FDA approved><Funding><Genetic mutation><Grant><Human><Ig Variable Region><Immunoglobulin V><Immunoglobulin Variable Region><In Situ><In Vitro><Individual><Investments><Libraries><Ligand Binding><Ligands><Malignant Neoplasms><Malignant Tumor><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular Dynamics Simulation><Molecular Interaction><Murine><Mus><NCI Organization><National Cancer Institute><Oncogene Products><Oncogene Proteins><Oncoproteins><PK/PD><Patients><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pneumonia><Production><Proteins><Receptor Protein><Reporting><Research Design><Resistance to antibiotics><Resistant to antibiotics><SARS><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sequence Alteration><Series><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Structure-Activity Relationship><Study Type><Technology><Therapeutic><Ursidae><Ursidae Family><Vaccines><Variable Region><Variant><Variation><Virus><Work><Wuhan coronavirus><antibiotic drug resistance><antibiotic resistant><bear><chemical structure function><comparative><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><design><designing><developmental><drug/agent><genomic alteration><in vivo><inhibitor><inhibitor/antagonist><malignancy><model of animal><model organism><molecular dynamics><mouse model><murine model><nano systems><nanosystems><neoplasm/cancer><neutralizing antibody><non-natural amino acids><non-proteinogenic amino acids><nonproteinogenic amino acids><pathogen><pharmacokinetics and pharmacodynamics><pre-clinical><preclinical><programs><receptor><recruit><response><screening><small molecule><structure function relationship><study design><therapeutic candidate><unnatural amino acids>