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Principal Investigator: Matteo Porotto
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2021
Award: $561,162
Funding agency: National Institute of Allergy and Infectious Diseases
Measles (MeV) causes disease worldwide despite efforts towards eradication by
vaccine, largely because it is spread so readily between people. Acute MeV infection
causes immune amnesia, resulting in increased susceptibility to other infectious
diseases. In addition, rare but severe neurological complications can develop several
years after measles due to persistent MeV infection of the central nervous system.
People with impaired cellular immunity are at increased risk of developing severe
measles, but often cannot be vaccinated since the vaccine virus itself can lead to fatal
illness. There is no specific therapy for acute or persistent MeV manifestations. A
successful vaccination campaign could have eradicated MeV more than 20 years ago.
As today, mainly due to social issue (e.g., antivaxxer movement), eradication is not in
sight. The recent resurgence of measles in the U.S. highlights the need of effective
measure to prevent host-to-host transmission at the moment of the outbreak surge.
We have applied the results of fundamental research to develop a new antiviral strategy
for MeV, based on inhibiting membrane fusion during MeV entry. This application will
test whether our antiviral approach prevents inter-host transmission and therefore fill this
medical demand. Our strategy is based MeV fusion inhibitors (i.e., lipid conjugated
peptides) that self-assemble in stable nanoparticles until they reach the target cells
were, they integrated into the cell membrane.
We have recently shown that this strategy works effectively for SARS-CoV-2.
We propose to chemical engineer these inhibitors to optimize 1) the antiviral potency, 2)
the conditions under which the peptides self-assemble, 3) the insertion on the target cell
membrane, and 5) in vivo biodistribution.
Our work will be tested in vitro, ex vivo, and in vivo using a natural model of morbillivirus
infection (Canine Distemper Virus -CDV- in Ferrets).
1. To use protein engineering to optimize the self-assembling properties and
antiviral potency of HRC-peptide fusion inhibitors.
2. To evaluate the protection afforded by HRC peptide fusion inhibitors against
CDV infection in vivo and provide proof of concept for pre-clinical development.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Address><Amnesia><Amnesia-Memory Loss><Animal Model><Animal Models and Related Studies><Animals><Antiviral Agents><Antiviral Drugs><Antivirals><Biodistribution><Brain Inflammation><C-terminal><CD150><CD150 antigen><CDw150 protein><CNS infection><COVID-19 virus><COVID19 virus><Canine Distemper Virus><Canine Species><Canis familiaris><Cell Body><Cell Mediated Immunology><Cell membrane><Cell-Mediated Immunity><Cells><Cellular Immunity><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Chemical Engineering><Child><Child Youth><Childhood><Children (0-21)><Chimera Protein><Chimeric Proteins><Clinical><CoV-2><CoV2><Communicable Diseases><Complex><Complication><Cyclicity><Cytoplasm><Cytoplasmic Membrane><Data><Disease><Disease Outbreaks><Disorder><Dogs><Dogs Mammals><EC 2.7.7.48><Encephalitis><Engineering><Epithelial Cells><Ethics><Ferrets><Fetus><Fusion Protein><General Population><General Public><Genome><Glycoproteins><Grant><Hemagglutinin><Hospital Admission><Hospitalization><Hydrophobicity><Immune><Immune system><Immunes><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><In Vitro><Individual><Infant><Infection><Infection prevention><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Interruption><Intranasal Administration><Intranasal Drug Administration><Kinetics><Lead><Lipids><Lung><Lung Respiratory System><Lymphoid Cell><Measles><Measles virus><Measures><Mediating><Medical><Membrane><Membrane Fusion><Modeling><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Morbilli Virus><Morbillivirus><Morbillivirus Infections><Mothers><Movement><Myeloid Cells><N-terminal><NH2-terminal><NIAID><National Institute of Allergy and Infectious Disease><Neurologic><Neurological><Non-Polyadenylated RNA><Nucleoproteins><Outbreaks><PRR protein><Paramyxoviridae><Paramyxovirus><Pathogenesis><Pb element><Peptides><Periodicity><Plasma Membrane><Play><Pneumonia><PrEP><Predisposition><Pregnant Women><Prevent infection><Primates><Primates Mammals><Property><Protein Engineering><Proteins><RNA><RNA Gene Products><RNA Replicase><RNA-Dependent RNA Polymerase><RNA-Directed RNA Polymerase><Receptor Protein><Recombinants><Reporter><Reporting><Research><Rhythmicity><Ribonucleic Acid><Ribonucleoproteins><Risk><Rodent><Rodentia><Rodents Mammals><Role><Rubeola><SARS corona virus 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><SLAM protein><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><Sight><Structure><Susceptibility><Testing><Toxic effect><Toxicities><Translating><Transmission><United States><Vaccinated><Vaccination><Vaccines><Vertical Disease Transmission><Vertical Transmission><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus><Virus Diseases><Vision><Work><Wuhan coronavirus><allergic/immunologic body system><allergic/immunologic organ system><anti-viral agents><anti-viral drugs><anti-virals><attenuated measles virus><base><biophysical analysis><biophysical studies><block viral entry><body movement><canine><conformation><conformational state><coronavirus disease 2019 virus><design><designing><dimer><domestic dog><ethical><expectant mother><expecting mother><fundamental research><genetic protein engineering><hCoV19><heavy metal Pb><heavy metal lead><human disease><immune suppression><immunosuppressed patient><in vitro testing><in vivo><inhibit viral entry><inhibitor><inhibitor/antagonist><low income country><membrane structure><model of animal><model organism><morbilli><mortality><mother to child transmission><nCoV2><nano particle><nano-sized particle><nanoparticle><nanosized particle><nectin><non-human primate><nonhuman primate><pediatric><plasmalemma><pre-clinical development><pre-exposure prophylaxis><preclinical development><pregnant mothers><prevent><preventing><protein design><pulmonary><receptor><rougeole virus><rubeola virus><self assembly><signaling lymphocytic activation molecule><signaling lympocyte activation molecule><social><social role><transmission process><viral entry blocker><viral entry inhibitor><viral infection><viral transmission><virus infection><virus transmission><virus-induced disease><visual function><youngster>