Broad spectrum inhibitors of paramyxovirus envelope proteins

Active Project Grant Awarded Last action

Award ID
R01AI175362
Recipient
Awarding agency
Obligated
$7,686,263

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 81% complete
Place of performance
New York, NY 10032, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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 a-amino acid residues with unnatural SS-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.

Transactions

Action Obligated Date
Amendment $717,050
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Amendment $35,902
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Amendment $848,745
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Original award $848,745
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Subawards

Subrecipient Amount Awarded
Trustees Of Boston University "Subaward Principal Investigator: Robert A. Davey, PhD In vivo work involves golden hamster and African green monkey (AGM) disease model development and… $141,382
The Ohio State University "In vivo work involves golden hamster and African green monkey (AGM) disease model development and efficacy testing. We anticipate running 6 efficacy studies in… $141,660
Institut National De La Sante Et De La Recherche Medicale "Within the project “Broad spectrum inhibitors of paramyxovirus envelope proteins” I shall coordinate and oversee the in vitro and in vivo experimentation… $54,000
University Of Washington The Greninger lab will provide deep sequencing of Paramyxovirus in the presence or absence of inhibitor as proposed in this project. Our lab will construct… $706,000
The Ohio State University “Broad spectrum inhibitors of paramyxovirus envelope proteins� Dr. Niewiesk’s laboratory will perform all cotton rat work proposed in the… $70,875
University Of Washington The Greninger lab will provide deep sequencing of Paramyxovirus in the presence or absence of inhibitor as proposed in this project. Our lab will construct… $70,600

Quick answers

Who received award R01AI175362?

R01AI175362 was awarded to The Trustees Of Columbia University In The City Of New York by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on August 1, 2023.

How much is award R01AI175362 worth?

$7,686,263 has been obligated on R01AI175362.

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