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Principal Investigator: Anne Moscona
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $41,396
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
Human parainfluenza viruses (HPIV) cause a significant portion of childhood croup, bronchiolitis and
pneumonia in the U.S. and worldwide, yet no effective drugs or vaccines are available. For the lethal Nipah
(NiV) and Hendra (HeV) viruses, in the face of human-to-human transmission of NiV, there is risk for global
spread as well as accidental or deliberate exposure. Despite the existence of antibody preparations for passive
immunoprophylaxis, there is no feasible approach to prevent or treat the human disease. These viruses serve
as prototypes for emerging paramyxoviruses. With this application we build on recent breakthroughs that have
led to a new broad-spectrum antiviral strategy based on inhibiting fusion during viral entry. We combine
structure-based optimization of fusion inhibitory lipopeptides, backbone modification via partial replacement of
α-amino acid residues with unnatural β-amino acid residues to enhance half-life, and addition of lipid
components to enhance antiviral efficacy. Using virologic, ex vivo, and in vivo experiments we will develop
powerful novel HPIV3/NiV/HeV fusion inhibitors that can be administered by inhalation. Validation of our
strategies with circulating respiratory viruses and clinical NiV virus strains in vitro and in vivo will lead us to
antiviral agents that are effective and practical in the clinical setting.
Aim 1. Targeting the paramyxovirus fusion complex: Evaluate entry inhibitor approaches in vitro.
We will develop fusion-inhibitory lipopeptides, combining conventional peptide design with backbone-
modification and membrane targeting to optimize broad fusion inhibition activity for NiV, HeV, HPIV, and
optimize potency, protease resistance, and tissue targeting of lead lipopeptides. We will evaluate antiviral
activity and potential for antiviral resistance in authentic ex vivo models. Human airway and brain models will
be employed to elicit resistant viruses in ex vivo evolution experiments, to study the molecular bases for
antiviral activity and potential for resistance to lead peptides.
Aim 2. Pharmacokinetics, biodistribution and efficacy of formulated lead antivirals in vivo.
We will assess the biodistribution and immunogenicity, acute toxicity, and PK/PD via nasal or inhalation
delivery of lead candidate series in small animal models, and evaluate efficacy of lead peptides for NiV/HeV in
golden hamsters and for HPIV in cotton rats. An efficacy study for the NiV lead will be conducted in African
green monkeys.
We propose that peptide backbone modification and membrane targeting strategies will generate broad anti-
paramyxovirus agents that can be delivered via inhalation with unprecedented efficacy and pharmacokinetic
properties.
Terms: <0-11 years old><Accidents><Acute Obstructive Laryngitis><Acylneuraminyl hydrolase><African Green Monkey><Amino Acids><Animal Model><Animal Models and Related Studies><Animals><Anti-viral Agents><Anti-viral resistance><Antibodies><Assay><Binding Proteins><Bioassay><Biodistribution><Biological Assay><Body Tissues><Brain><Brain Nervous System><Bronchiolitis><Cell Body><Cell membrane><Cells><Cessation of life><Child><Child Youth><Childhood><Children (0-21)><Chimera Protein><Chimeric Proteins><Chlorocebus aethiops><Chlorocebus sabaeus><Clinical><Complex><Cotton Rats><Croup><Cytoplasmic Membrane><Death><Drug Kinetics><Drugs><Encephalon><Ensure><Envelope Protein><Equine Morbillivirus><Esteroproteases><Evolution><Family><Finding by Cause><Fusion Protein><Genetic Alteration><Genetic Change><Genetic defect><Glycoproteins><Goals><Golden Hamsters><Golden Syrian Hamsters><Green Monkey><HPIV3><Half-Life><Health><Hemadsorption Virus 1><Hemagglutinin><Hendra><Hendra Virus><Hendra henipavirus><Henipavirus><Human><Human Parainfluenza Virus 3><In Vitro><Infant><Infection><Inhalation><Inhalation Administration><Inhalation Drug Administration><Inhalation Route of Drug Administration><Inhaling><Interruption><Lead><Ligand Binding Protein><Ligand Binding Protein Gene><Lipids><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Mediating><Medication><Membrane><Membrane Fusion><Mesocricetus auratus><Methods><Modeling><Modern Man><Modification><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mutation><N-Acylneuraminate Glycohydrolases><Nasal><Nasal Passages Nose><Neuraminidase><Nipah Virus><Nipah henipavirus><Nose><Oligosaccharide Sialidase><Organoids><PK/PD><Para-Influenza Virus Type 3><Paramyxoviridae><Paramyxovirus><Pb element><Peptidases><Peptide Hydrolases><Peptides><Pharmaceutical Preparations><Pharmacokinetics><Plasma Membrane><Pneumonia><Position><Positioning Attribute><Preparation><Property><Protease Gene><Proteases><Protein Binding><Proteinases><Proteins><Proteolytic Enzymes><Receptor-Interacting Protein><Resistance><Resistance development><Resistant development><Respiratory Drug Administration><Respiratory System, Nose, Nasal Passages><Risk><Rodent><Rodentia><Rodents Mammals><Self Administered><Self Administration><Series><Sialidase><Site><Spinal Column><Spine><Structure><Structure of parenchyma of lung><Syrian Hamsters><System><Therapeutic><Tissue Model><Tissues><Transmission><Validation><Vertebral column><Viral><Viral Activity><Viral Function><Viral Physiology><Virus><access to vaccination><access to vaccines><acute toxicity><aminoacid><anti-viral compound><anti-viral drugs><anti-viral efficacy><anti-viral medication><anti-viral resistant><anti-viral therapeutic><anti-virals><appendage><backbone><base><bases><block viral entry><bound protein><combat><conformation><conformational><conformational conversion><conformational state><conformational transition><conformationally><conformations><design><designing><determine efficacy><developing resistance><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy study><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate efficacy><examine efficacy><exo alpha sialidase><experiment><experimental research><experimental study><experiments><fundamental research><genome mutation><heavy metal Pb><heavy metal lead><human disease><immunogenicity><improved><in vivo><inhibit viral entry><inhibitor><innovate><innovation><innovative><kids><lead candidate><membrane structure><model of animal><novel><parainfluenza virus><parainfluenza virus type 3><passive immunoprophylaxis><pathogenic virus><pediatric><peptide aminoacid sequence><peptide sequence><pharmacokinetics and pharmacodynamics><plasmalemma><preparations><prevent><preventing><prophylactic><protein aminoacid sequence><prototype><pulmonary><receptor binding><receptor bound><resistance mechanism><resistant><resistant mechanism><respiratory virus><transmission process><vaccination access><vaccination availability><vaccine access><vaccine availability><validations><viral entry blocker><viral entry inhibitor><viral pathogen><viral resistance><virus pathogen><virus resistance><youngster>