Document text
Principal Investigator: Jim Rotolo
Organization: SAPIENCE THERAPEUTICS, INC.
Fiscal Year: 2022
Award: $288,178
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is a serious threat to global public health,
necessitating the rapid development of safe and effective medical countermeasures. SARS-CoV-2 pathogenicity
requires a series of protein-protein interactions (PPI) involving the virus’ S protein that leads to virus attachment
and fusion. Initially, the receptor binding domain (RBD) on the S protein S1 subunit binds to ACE2 receptors on
the host cell. This triggers a conformational change in the S protein S2 subunit, driving the viral heptad repeat 1
(HR1) and heptad repeat 2 (HR2) domains of S2 to form a six-helical bundle (6-HB), enabling the viral envelope
to be brought in close proximity to the host membrane, thus promoting viral fusion. Peptides have emerged
recently as a therapeutic class capable of targeting and disrupting PPI with high affinity and specificity. We
hypothesize antagonism of the virus S protein with a peptide therapeutic will provide an effective anti-viral
strategy for SARS-CoV-2 infection, and potentially a pan-coronavirus intervention. We propose a plan to select
a lead candidate peptide antagonist based upon target binding and viral neutralization in vitro, with consideration
of escape mutants, and attenuation of virus load and shedding in a ferret challenge model in vivo. Successful
completion of this program will support advancement of the lead candidate peptide to IND-enabling studies, and
provide the rationale for submission of a Phase II SBIR proposal to evaluate inhalation delivery for severe
respiratory disease.
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therapeutics><COVID19 therapy><COVID19 treatment><COVID19 virus><Cell Body><Cells><CoV anti-viral><CoV antiviral><CoV disease><CoV-2><CoV2><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Data><Development><Dose><ELISA><Electrostatics><Engineering><Ensure><Enzyme-Linked Immunosorbent Assay><Escape Mutant><Evaluation><Ferrets><Future><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genome><HIV-1><HIV-I><HIV1><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><In Vitro><Infection><Inhalation><Inhaling><Intervention><Intervention Strategies><Invaded><Lead><Length><Measures><Membrane><Methods><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Sieve Chromatography><Molecular Stereochemistry><Mutation><Non-Polyadenylated RNA><Organelles><Pathogenicity><Pb element><Peptide Domain><Peptide-based drug><Peptides><Phase><Physiologic Availability><Protein Domains><Proteins><Public Health><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA><RNA Gene Products><Receptor Protein><Resistance><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Ribonucleic Acid><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><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><SBIR><Series><Severe Acute 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respiratory syndrome coronavirus 2 therapeutics><Severe acute respiratory syndrome related corona virus 2><Size Exclusion Chromatography><Small Business Innovation Research><Small Business Innovation Research Grant><Specificity><Surface Plasmon Resonance><Tertiary Protein Structure><Testing><Therapeutic><Therapeutic Intervention><Validation><Vero Cells><Viral><Viral Burden><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Load><Viral Load result><Viral Proteins><Viral Shedding><Viral load measurement><Virus><Virus Diseases><Virus Shedding><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><angiotensin converting enzyme 2><angiotensin converting enzyme II><antagonist><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-viral therapy><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><attenuation><base><beta CoV><beta 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