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Novel antiviral strategy offering forward capability and reduced risk of escape

Award Number: R21AI168934
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/04/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Novel antiviral strategy offering forward capability and reduced risk of escape - ABSTRACT The current coronavirus (CoV) pandemic, seasonal infections by other CoV and other “cold” viruses, plus the need for annual influenza vaccinations exemplify the challenges posed by viral antigenic drift and shift. Targeting landscapes of viral structural proteins displayed on the surfaces of virus particles and or the surfaces of infected cells has been the primary basis for developing antibody-based therapeutics. Although great advances have been made in trying to identify regions of these surface displayed proteins that are conserved and less prone to “escape” antibody binding, it appears to be a continual battle of cat and mouse as we are seeing with continual emergence of CoV “Variants of Concern”. In contrast, viral structural proteins that remain inside virus particles and cells, avoid the impact of cyclical antibody selection, and tend to be far more conserved. Oligomeric assemblies of these proteins can also blunt the impact of antiviral escape mutations owing to the mix of mutant and wild-type monomers present in the parent cell. Furthermore, the stoichiometry required of an antiviral to impede oligomer function need not be necessarily 1 antiviral to 1 monomer since, especially if the antiviral were a crosslinker, its impact would be relayed beyond the immediate contact to neighboring oligomers. Our long-term hypothesis is that affinity reagents capable of binding an internal oligomeric structural protein of all species of a viral genus uniformly will impede viral assembly when present as dimeric crosslinkers in a manner that is both forward capable and has much reduced susceptibility to viral escape. We will explore the antiviral potential of dimeric crosslinkers using viruses of the genus Ebolavirus as our model and a novel, rare nanobody manifesting uniform reactivity to nucleoprotein of all 6 species. Our two specific aims are: (1) we will engineer mammalian cell expression vectors encoding nanobody homodimers and assess antiviral activity using virus like particle surrogates at BSL-2 following plasmid transfection to drive intrabody expression, (2) we will engineer E. coli expression vectors encoding nanobody homodimers fused to cell penetrating peptides and glycosaminoglycan binding motifs and assess antiviral activity following protein transduction of virus infected cells at BSL-4. Success will demonstrate a novel antiviral strategy that can then be thoroughly explored for the propensity to select escape mutants relative to an existing neutralizing antibody regime to test whether the strategy is more “escape-proof”. The overall approach should be applicable to other human viral pathogens by carefully retuning the affinity reagent, with adequate time and resources, to maximize broad long-term impact in helping to safe guard human health.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	1/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $247,500 )
2024	2024	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	001	2	3/27/2024	NON-COMPETING CONTINUATION	$247,500
2024	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	2/21/2024	NEW	$0
														Subtotal = $247,500

Issue Date FY: 2023 ( Subtotal = $297,000 )
2023	2023	TEXAS BIOMEDICAL RESEARCH INSTITUTE	8715 W MILITARY DR	SAN ANTONIO	TX	78227	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	4/4/2023	NEW	$297,000
														Subtotal = $297,000

Grand Total All Awards = $544,500

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Novel antiviral strategy offering forward capability and reduced risk of escape

Award Number: R21AI168934

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/04/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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