The ultimate goal of this Phase I application is to discover and develop host-oriented small molecule compounds targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 is a novel coronavirus driving the current global pandemic of severe respiratory syndrome in humans. Antiviral therapeutics are urgently needed to combat infection by SARS-CoV-2 and new variants that are continuing to emerge. We have discovered several chemical series that target modular interactions between specific host proteins containing WW-domains (e.g. Nedd4) and viral proteins containing PPxY motifs (e.g. Ebola VP40). Notably, emerging RNA virus pathogens such as Ebola, Marburg, Lassa, and rabies viruses all encode PPxY motifs that recruit host WW-domain containing proteins to facilitate efficient virus egress, spread, and transmission. Interestingly, the surface-exposed Spike glycoprotein (S) of SARS-CoV-2 also has a putative WW-domain binding motif (25PPAY28), that is not present in the S protein of SARS-CoV-1 or more attenuated coronavirus strains. The acquisition of this PPAY motif in the major surface protein of SARS-CoV-2 virions raises the intriguing possibility that it may contribute to the unique pathogenicity and/or transmission of SARS-CoV-2 via interactions with specific host WW-domain bearing proteins. In our ongoing studies on filoviruses and arenaviruses, we have used extensive SAR to identify a lead compound series capable of blocking egress and spread of live EBOV, MARV, and LAFV in cell culture, as well as blocking disease progression in vivo in a live MARV challenge model. Here, we hypothesize that "informed" SAR analyses of our in-hand PPxY/WW-domain inhibitors (e.g. lead candidate FC-10696) will lead to the discovery of analogs capable of blocking egress and disease progression of SARS-CoV-2, as well as related PPxY-containing variants that may emerge in the future. In support of our hypothesis, we present strong preliminary data showing that the PPxY motif within the S protein of SARS-CoV-2 virus can interact with host WW-domain containing proteins that are known to promote egress and spread of EBOV, MARV, and LAFV. Moreover, our current lead candidate PPxY budding inhibitors show activity in blocking egress of live SARS-CoV-2 virus infection in human lung epithelial cells. In this Phase I proposal, we will identify and evaluate host-oriented inhibitors as potential therapeutics for SARS-CoV-2 and related coronaviruses by combining the pharmaceutical and medicinal chemistry expertise of the scientists at the Fox Chase Chemical Diversity Center, Inc. (FCCDC) with the expertise and experience of the Harty Lab at the University of Pennsylvania in the experimental aspects of virus-host interactions and antiviral therapy, and the lab of Olena Shtanko at Texas Biomedical Research Institute for evaluating compounds against live viruses under BSL-3 conditions. The three aims are (1) lead finding and optimization medicinal chemistry including ADME profiling, (2) evaluation for the ability to specifically inhibit egress of SARS-CoV-2 VLPs and PPxY- mediated S-host protein interactions, and (3) in vitro and in vivo analyses against authentic SARS-CoV-2 virus.
Public Health Relevance Statement: There is an urgent need to develop antiviral therapies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its emerging variants such as Omicron. We have been successful in discovering small molecule compounds that disrupt budding and spread of emerging RNA viruses including Ebola, Marburg, and Lassa fever viruses; a process that is critical for virus dissemination and disease progression. Here, we will use our established expertise in medicinal chemistry and virus budding assays to adapt and develop these host-oriented, antiviral budding inhibitors to target SARS-CoV-2 virus egress and transmission.
Project Terms: inhibitor; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral compound; anti-viral drugs; anti-viral medication; anti-viral therapeutic; anti-virals; antiviral compound; antiviral medication; antiviral therapeutic; Automobile Driving; driving; Biological Assay; Assay; Bioassay; Biologic Assays; Biomedical Research; Cell Culture Techniques; cell culture; cell cultures; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Ebola virus; EBOV; Ebola-like Viruses; ebolavirus; Epithelial Cells; Foxes; Future; Glycoproteins; Goals; Hand; Human; Modern Man; In Vitro; Lassa virus; Lassa fever virus; Lead; Pb element; heavy metal Pb; heavy metal lead; Lung; Lung Respiratory System; pulmonary; Marburgvirus; Frankfurt-Marburg Syndrome Virus; Marburg; Marburg virus; Marburg-like Viruses; Membrane Proteins; Membrane Protein Gene; Membrane-Associated Proteins; Surface Proteins; Mus; Mice; Mice Mammals; Murine; Pennsylvania; Plasma Proteins; Proteins; Rabies virus; Research Institute; RNA Viruses; Solubility; Syndrome; Texas; Universities; Viral Proteins; Viral Gene Products; Viral Gene Proteins; virus protein; Virion; Virus Particle; Virus Diseases; Viral Diseases; viral infection; virus infection; virus-induced disease; Virus; Mediating; Surface; Phase; Variant; Variation; Series; Coronavirus; Coronaviridae; corona virus; Arenavirus; Arenaviridae; Arenavirus group; Filovirus; Filoviridae; Chemicals; Evaluation; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Disease Progression; analog; anti-viral therapy; viral infectious disease treatment; Antiviral Therapy; CaCo2; Caco-2 Cells; Metabolic; Attenuated; Scientist; Investigation; Oral; respiratory; gastrointestinal; meetings; experience; virus host interaction; Toxicities; Toxic effect; disorder model; Disease model; Modeling; Property; Pathogenicity; Molecular Interaction; Binding; SARS Virus; SARS corona virus; SARS-Associated Coronavirus; SARS-CoV; SARS-CoV-1; SARS-Related Coronavirus; Severe Acute Respiratory Coronavirus; Severe Acute Respiratory Syndrome Virus; Severe Acute Respiratory Syndrome corona virus; Severe Acute Respiratory Syndrome coronavirus; severe acute respiratory syndrome-CoV; SARS coronavirus; small molecule; Data; in vivo; Small Business Technology Transfer Research; STTR; transmission process; Transmission; Process; Development; developmental; pandemic disease; pandemic; scale up; mouse model; murine model; therapeutic target; combat; anti-viral efficacy; antiviral efficacy; recruit; lead optimization; lead candidate; in vivo evaluation; in vivo testing; pathogenic virus; viral pathogen; virus pathogen; novel coronavirus; CoV emergence; corona virus emergence; coronavirus emergence; emergent CoV; emergent corona virus; emergent coronavirus; emerging CoV; emerging corona virus; emerging coronavirus; nCoV; new CoV; new corona virus; new coronavirus; novel CoV; novel corona virus; 2019-nCoV; 2019 novel corona virus; 2019 novel coronavirus; COVID-19 virus; COVID19 virus; CoV-2; CoV2; SARS corona virus 2; SARS-CO-V2; SARS-COVID-2; SARS-CoV-2; SARS-CoV2; SARS-associated corona virus 2; SARS-associated coronavirus 2; SARS-coronavirus-2; SARS-related corona virus 2; SARS-related coronavirus 2; SARSCoV2; 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-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 related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; Ebola; COVID-19 therapeutics; COVID19 therapeutics; SARS-CoV-2 therapeutics; SARS-coronavirus-2 therapeutics; Severe acute respiratory syndrome coronavirus 2 therapeutics; coronavirus disease 2019 therapeutics; 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; ACE2; angiotensin converting enzyme 2; angiotensin converting enzyme II; SARS-CoV-2 transmission; COVID-19 transmission; COVID-19 virus transmission; coronavirus disease 2019 transmission; coronavirus disease 2019 virus transmission; severe acute respiratory syndrome coronavirus 2 transmission; transmitted COVID-19; transmitted SARS-CoV-2; transmitted coronavirus disease 2019; transmitted severe acute respiratory syndrome coronavirus 2; SARS-CoV-2 infection; COVID-19 infection; COVID19 infection; SARS-CoV2 infection; Severe acute respiratory syndrome coronavirus 2 infection; coronavirus disease 2019 infection; 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; SARS-CoV-2 inhibitor; Severe acute respiratory syndrome coronavirus 2 inhibitor; block SARS-CoV-2; block severe acute respiratory syndrome coronavirus 2; inhibit SARS-CoV-2; inhibit severe acute respiratory syndrome coronavirus 2; antiviral drug development; anti-viral development; anti-viral drug development; anti-viral therapeutic development; anti-viral therapy development; antiviral development; antiviral therapeutic development; antiviral therapy development; developing anti-viral agent; developing anti-viral drug; developing anti-viral therapeutic; developing anti-viral therapy; developing antiviral agent; developing antiviral drug; developing antiviral therapeutic; developing antiviral therapy
