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Principal Investigator: PETER SARNOW
Organization: STANFORD UNIVERSITY
Fiscal Year: 2022
Award: $4,810,759
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The overall objective of this project is to use an integrated, multidisciplinary research endeavor that brings
together investigators with expertise in diverse areas to advance the development of novel targets, therapeutic
strategies, and delivery methods to treat viral pathogens of pandemic concerns, such as SARS-CoV-2 and
enterovirus 71. The central hypothesis is that a combination of interdisciplinary expertise in virology, chemistry,
viral RNA structure and dynamics and therapeutic delivery will reveal novel Achille’s heals in viral genomes.
Roles for novel structural targets in linear viral RNA and in recently discovered viral genome-derived circular
RNAs will be studied, using novel small molecules that target distinct structures in RNAs. The mode of actions
of RNA-targeting small molecules will be extended using ribonuclease targeting chimeras, or RIBOTACs, that
destroy target RNAs. A combination of synthetic mRNA-encoded Cas13, which is an activable ribonuclease
(RNase), and guide RNAs, in conjunction with nebulizer-based lung delivery will enable us to control the amount
of the RNase available, as it is not reliant on endogenous RNases. Nucleic acid-based therapeutics can be
used to modulate any desired gene. However, the nucleic acid must enter the cell, which requires a drug
delivery system. Here, we will use two complementary delivery systems: (i) Microvesicle-mediated delivery.
ARRDC1-mediated microvesicles (ARMMs) are a promising drug delivery system, where multiple cargo
molecules can be packaged concurrently and reproducibly, offering the potential to use ARMMs to concurrently
deliver multiple nucleic acid cargos that can target multiple viral species or variants. Thus, ARMMs offer an
innovative method for packaging and delivery of antiviral RNAs. (ii) Next-generation lipid nanoparticles (LNPs),
in conjunction with nebulizer-based lung delivery. We will improve LNP-mediated nucleic acid delivery by
changing the LNP composition to ensure that the LNPs are clinically relevant, and we will only test chemically
simple, biodegradable, scalable, and stereopure lipids. The tremendous clinical impact of the LNP-mRNA
vaccines and other LNP-RNA drugs underscores the acute need for next-generation LNPs with improved
therapeutic windows or tropism to new cell types. To achieve these goals, Project 2 will interact with the
Pandemic Assistance Core Structural Biology Core and the Translation Accelerator Core. Further, this
project forms key bridge for the delivery of therapeutics in Project 1 (LNAs), Project 3 (peptides, peptoids, and
degraders that target viral envelopes and surface proteins), Project 4 (PROTACs that degrade viral proteins),
Project 5 (protease inhibitors), and Project 6 (nucleoside analogs). The expected outcomes from our rigorous,
validated data will enable the execution of our aims to identify novel targets, to employ novel therapeutic
strategies, and to apply novel delivery systems of antivirals against SARS-CoV-2, EV-71, and other viral
pathogens of pandemic concern.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><Acute><Adult><Adult Human><Advanced Development><Animal Model><Animal Models and Related Studies><Animals><Antiproteases><Antiviral Agents><Antiviral Drugs><Antivirals><Area><Base Sequence><Binding><Biochemical><COVID-19 infection><COVID-19 virus><COVID19 infection><COVID19 virus><Cell Body><Cell Culture Techniques><Cell model><Cells><Cellular model><Chemicals><Chemistry><Chimera><Chimera organism><Clinical><CoV-2><CoV2><Cold Chains><Collaborations><Coronaviridae><Coronavirus><Cricetinae><Custom><Data><Development><Devices><Disease model><Dose><Drug Delivery><Drug Delivery Systems><Drug Precursors><Drug Stability><Drugs><Endopeptidase Inhibitors><Ensure><Enterovirus 71><Evaluation><Family Picornaviridae><Gene Expression><Gene Transcription><Genes><Genetic><Genetic Transcription><Genome><Goals><Guide RNA><HCV><Hamsters><Hamsters Mammals><Hepatitis C virus><Human><IRES><Immunology><In Vitro><Interdisciplinary Research><Interdisciplinary Study><Internal Ribosome Entry Segment><Internal Ribosome Entry Site><Investigators><Libraries><Lipids><Lung><Lung Respiratory System><Mediating><Medication><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Methods><Mice><Mice Mammals><Modern Man><Modification><Molecular Interaction><Multidisciplinary Collaboration><Multidisciplinary Research><Murine><Mus><Nebulizer><Non-Polyadenylated RNA><Nucleic Acids><Nucleotide Sequence><Out-patients><Outcome><Outpatients><Pancreatic RNase><Pancreatic ribonuclease><Pattern><Peptidase Inhibitors><Peptide Hydrolase Inhibitors><Peptide Peptidohydrolase Inhibitors><Peptides><Peptoids><Pharmaceutic Preparations><Pharmaceutical Preparations><Picornaviridae><Picornaviruses><Pro-Drugs><Process><Prodrugs><Protease Antagonists><Protease Inhibitor><Proteinase Inhibitors><Proteins><RNA><RNA Binding><RNA Expression><RNA Gene Products><RNA Nucleases><RNA Viruses><RNA bound><RNA vaccine><RNA-based vaccine><RNase><RNase A><RNase I><Regulatory Element><Reporting><Research Personnel><Researchers><Resistance><Ribonuclease A><Ribonuclease Family Protein><Ribonuclease I><Ribonucleases><Ribonucleic Acid><Ribosome Entry Site><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><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 coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Site><Structure><Surface Proteins><System><Technology><Testing><Therapeutic><Transcript><Transcription><Translating><Translations><Tropism><Variant><Variation><Vesicle><Viral><Viral Envelope Proteins><Viral Gene Products><Viral Gene Proteins><Viral Genes><Viral Genome><Viral Proteins><Virulence><Virus><Work><Wuhan coronavirus><adulthood><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><base><biological systems><biophysical approaches><biophysical methodology><biophysical methods><biophysical techniques><cell culture><cell cultures><cell type><circular RNA><clinical relevance><clinically relevant><closed circular RNA><corona virus><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><design><designing><developmental><disorder model><drug/agent><emerging pathogen><extracellular vesicles><gRNA><hCoV19><healing><improved><in vivo><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><innovate><innovation><innovative><lipid based nanoparticle><lipid nanoparticle><locked nucleic acid><lung basal segment><lung base><mRNA><mRNA delivery><mRNA vaccine><mRNA-based vaccine><microvesicles><model of animal><model organism><molecular recognition><nCoV2><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><new pathogen><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><next generation><novel><novel pathogen><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nucleic acid delivery><nucleic acid sequence><nucleic acid therapy><nucleic acid-based therapeutics><nucleoside analog><pandemic><pandemic disease><pathogen><pathogenic virus><pre-clinical study><preclinical study><pulmonary><recruit><resistant><screening><small molecule><social role><structural biology><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic nucleic acids><viral RNA><viral pathogen><viral resistance><virology><virus RNA><virus genome><virus pathogen><virus protein><virus resistance>