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Principal Investigator: Robert G Lowery
Organization: BELLBROOK LABS, LLC
Fiscal Year: 2021
Award: $390,500
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
SARS CoV-2 and related coronaviruses hijack host proteins to facilitate cell entry, replication and
immune suppression. Targeting hijacked host proteins is an attractive strategy for development
of broad-spectrum antiviral drugs because the same proteins are often targeted by multiple
viruses. A global SARS-CoV-2/human protein/protein interaction analysis recently revealed one
such target: the human acyltransferase DHHC5, which catalyzes palmitoylation of proteins to
regulate trafficking in the endocytic pathway, was shown to interact with the SARS-CoV-2 Spike
protein. This finding was exciting in itself, but in light of multiple lines of evidence indicating that
DHHC5’s role in localizing proteins at the plasma membrane is hijacked by diverse pathogens to
gain entry into the cell, it is compelling rationale for developing DHHC5 inhibitors to test as
antivirals.
We propose to develop selective DHHC5 inhibitors as lead molecules to test in animal models of
coronavirus infection. Currently, the tools for a small molecule drug discovery effort for this target
are lacking: there is very little structural information on DHHC family members and no robust HTS
assays. The goals of this R21 proposal are to develop and validate the tools needed for discovery
of DHHC5 inhibitors and initiate a lead discovery program. To address this, we will develop and
validate a robust, quantitative high throughput DHHC5 enzymatic assay based on a coupled
fluorescence polarization immunoassay (FPIA) that will serve as a critical tool for screening and
performing hit-to-lead/SAR studies. We will use the assay to screen a diversity library, validate
the hits and prioritize them based on physicochemical properties, potency, selectivity, mechanism
of action and functional activity. Additionally, we will produce a cocrystal structure of DHHC5 in
complex with a validated hit molecule. Completion of these aims will establish technical feasibility
for pursuing a structure-driven design approach to discover lead molecules targeting DHHC5,
which could ultimately result in the development of antivirals with broad spectrum activity against
SARS-CoV-2 and coronavirus pathogens that emerge in the future.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Acyltransferase><Address><Animal Model><Animal Models and Related Studies><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><B anthracis LeTx><B anthracis LeTx toxin><Bacillus anthracis LF protein><Bacillus anthracis lef protein><Bacillus anthracis lethal toxin><Binding><Bioassay><Biochemical><Biologic Assays><Biological Assay><C-terminal><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cell Body><Cell membrane><Cells><Cellular Assay><Chemicals><CoA><CoV-2><CoV2><Coenzyme A><Collaborations><Communicating Junction><Complex><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coupled><Cytoplasmic Membrane><Detection><Development><Diversity Library><EC 2.3><Family member><Fluorescence Polarization Immunoassay><Future><Gap Junctions><Goals><Human><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Innate Immune System><Innate Immunity><Interferon Type I><Laboratories><LeTx><Lead><Libraries><Light><Low-resistance Junction><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Medicinal Chemistry><Methods><Mice><Mice Mammals><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><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Native Immunity><Natural Immunity><Nexus><Nexus Junction><Non-Specific Immunity><Nonspecific Immunity><Oxidation-Reduction><Pathway interactions><Pb element><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Photoradiation><Plasma Membrane><Polarization Fluoroimmunoassay><Property><Proprotein Convertases><Proteins><Receptor Protein><Redox><Resistance><Resolution><Roentgen Rays><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SBIR><Sampling><Screening procedure><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Small Business Innovation Research><Small Business Innovation Research Grant><Structure><Synthesis Chemistry><Synthetic Chemistry><Tail><Testing><Therapeutic><Toxin><Transgenic Mice><Triage><Virus><Wuhan coronavirus><X-Radiation><X-Ray Radiation><X-ray><Xray><aerolysin><angiotensin converting enzyme 2><angiotensin converting enzyme II><anthrax lethal factor><anthrax lethal toxin><anthrax toxin LF><anti-viral agents><anti-viral drugs><anti-virals><base><biophysical analysis><biophysical approaches><biophysical methodology><biophysical methods><biophysical studies><biophysical techniques><cell assay><computational chemistry><corona virus><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><design><designing><developmental><drug discovery><efficacy study><emerging pathogen><hCoV19><heavy metal Pb><heavy metal lead><immune suppression><in vivo><inhibitor><inhibitor/antagonist><lethal factor><lethal toxin><model of animal><model organism><mouse development><mouse model><murine model><nCoV2><new pathogen><novel pathogen><oxidation reduction reaction><palmitoylation><pathogen><pathway><plasmalemma><pre-clinical><preclinical><programs><protein protein interaction><receptor><resistant><screening><screening tools><severe acute respiratory syndrome-CoV><small molecule><social role><tool><trafficking>