Document text
Principal Investigator: Slobodan Paessler
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $626,423
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT ABSTRACT/SUMMARY
The viruses belonging to the family Arenaviridae contain several causative agents of hemorrhagic fever in
humans. For instance, Lassa virus causes Lassa fever, which is a major public health threat in endemic regions
of West Africa. Junin virus, Machupo virus, Guanarito virus, Sabia virus, and Chapare virus cause South
American hemorrhagic fevers, severe diseases in humans resulting in high fatality rates. These highly
pathogenic arenaviruses are classified as Risk Group-4 agents, which need to be handled in biosafety level-4
facilities due to their high pathogenicity and lack of vaccines or therapeutics. Additionally, arenaviruses causing
hemorrhagic fevers are listed on Category A Priority Pathogens because of the highest risk to national security
and public health. Thus, countermeasures, such as vaccines or antivirals, against arenavirus infections are
crucial medical needs globally.
Most antiviral agents are inhibitors of proteases or inhibitors of virus replication. In a search for alternative
approaches, we propose to study in more detail the dependence of arenavirus on metabolism of two key
monosaccharides, D-glucose and D-mannose. Our focus will be on using carbohydrate mimetics/antimetabolites
as antivirals. Specifically, we will employ isotopically labeled monosaccharides and molecular probes that
include 2-deoxy-D-glucose (2-DG), a D-glucose, and also a D-mannose analog as a reference compund, and
WP1096, a 2-iodo-D-mannose as a novel prototype carbohydrate antimetabolite antiviral. Our results will
enhance the success of designing future carbohydrate antimetabolite antiviral compounds as therapeutics to
alleviate suffering and contain arenaviral outbreaks.
We will address this goal through three specific aims.
Specific Aim 1. Determine the effect of WP1096 and 2-DG (as a control) on glycolysis pathways and viral
glycoproteins of tissue culture cells infected with arenaviruses (LASV, JUNV and MACV).
Specific Aim 2. In vivo evaluation of WP1096 that includes preclinical toxicology, tissue distribution,
pharmacokinetics, and analysis of active metabolites.
Specific Aim 3. Determine the in vivo protective efficacy of WP1096 and 2-DG (as a control) and analyze
their effects on glycosylation patterns and the host glycolysis pathway.
Taken together, we hope to develop promising pan-arenavirus therapeutics and gain the insight for development
of broad spectrum antivirals effective against multiple viral families.
Terms: <2-Deoxy-D-glucose><2-Deoxyglucose><2-Desoxy-D-glucose><2-deoxy-D-arabino-hexose><Aerobic><Aerosols><Affect><Africa><Animals><Anti-viral Agents><Antigenic Determinants><Antimetabolites><Antiproteases><Arenaviridae><Arenaviridae Infections><Arenavirus><Arenavirus Infections><Arenavirus group><Argentine hemorrhagic fever virus><Argentinian Hemorrhagic Fever Virus><Autopsy><BSL-4 facility><BSL4 facility><Binding><Binding Determinants><Biochemical><Bleeding><Blood Plasma><Body Tissues><Bolivian Hemorrhagic Fever Virus><Brain><Brain Nervous System><Cancers><Carbohydrates><Category A pathogen><Category A priority pathogen><Cell Body><Cell Culture Techniques><Cells><Chapare><Chapare Virus><Chemicals><Classification><Clinical><D-Glucose><D-Mannose><Deoxyglucose><Dependence><Development><Dextrose><Disease><Disease Outbreaks><Disorder><Dose><Drug Formulations><Drug Kinetics><Drug Targeting><Drug or chemical Tissue Distribution><Encephalon><Endopeptidase Inhibitors><Envelope Protein><Epitopes><FDA approved><Family><Fatality rate><Foundations><Future><Glucose><Glycans><Glycolysis><Glycolysis Induction><Glycolysis Inhibition><Glycolysis Pathway><Glycoproteins><Goals><Guanarito><Guanarito virus><Heart><Hemorrhage><Human><IP injection><Immune response><Immunological response><In vivo analysis><Intermediary Metabolism><Intraperitoneal Injections><Isotope Labeling><Junin><Junin virus><Kidney><Kidney Urinary System><LC/MS><Lassa Fever><Lassa disease><Lassa fever virus><Lassa virus><Liver><Lung><Lung Respiratory System><Machupo><Machupo virus><Malignant Neoplasms><Malignant Tumor><Mannopyranose><Mannopyranoside><Mannose><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Medical><Medicine><Metabolic Glycosylation><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Molecular Mimicry><Molecular Probes><Molecular Virology><Monosaccharides><Murine><Mus><National Security><Normal Cell><O element><O2 element><Organ><Outbreaks><Oxygen><Pathogenicity><Pathogenicity Factors><Pathologist><Pathway interactions><Pattern><Peptidase Inhibitors><Peptide Hydrolase Inhibitors><Peptide Peptidohydrolase Inhibitors><Pharmaceutical Agent><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Plasma><Plasma Serum><Polysaccharides><Process><Production><Proliferating><Property><Protease Antagonists><Protease Inhibitor><Protein Glycosylation><Proteinase Inhibitors><Proteins><Public Health><Receptor Cell><Reticuloendothelial System, Serum, Plasma><Risk><Route><Sabia virus><Secure><Sensorineural Deafness><Sensorineural Hearing Loss><Sensory Hearing Loss><South American Hemorrhagic Fever><Spleen><Spleen Reticuloendothelial System><Systematics><Testing><Therapeutic><Tissue Distribution><Tissues><Toxicology><Vaccines><Venezuelan hemorrhagic fever virus><Veterinarians><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Hemorrhagic Fevers><Viral Physiology><Virion><Virulence Factors><Virus><Virus Diseases><Virus Inhibitors><Virus Particle><Virus Replication><alternative treatment><analog><anti-cancer therapeutic><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><biosafety level 4 facility><blood loss><cell culture><cell cultures><design><designing><developmental><efficacy study><env Antigens><env Gene Products><env Polyproteins><env Protein><experiment><experimental research><experimental study><experiments><glycosylation><hemorrhagic fever><hepatic body system><hepatic organ system><high risk><host response><immune system response><immunoresponse><in vitro activity><in vivo><in vivo evaluation><in vivo testing><innovate><innovation><innovative><insight><liquid chromatography mass spectrometry><malignancy><mimetics><necropsy><neoplasm/cancer><novel><pandemic concern><pandemic potential><pandemic risk><pandemic threat><particle><pathway><pharmaceutical><postmortem><pre-clinical><preclinical><prevent><preventing><protective efficacy><prototype><pulmonary><renal><response><sensorineural hearing impairment><success><sugar><tissue/cell culture><treatment strategy><usability><viral infection><viral inhibitor><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease>