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High-throughput assays and small-molecule discovery of antiviral candidates targeting influenza hemagglutinin

Award Number: R01AI150885
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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High-throughput assays and small-molecule discovery of antiviral candidates targeting influenza hemagglutinin - PROJECT SUMMARY / ABSTRACT Influenza A viruses exhibit extreme diversity as exemplified by the multiple serotypes of the hemagglutinin (HA, H1-H18) and neuraminidase (NA, N1-N11) surface antigens. To date, only 3 of 198 possible combinations of HA and NA in avian and other animal reservoirs have been associated with human pandemics (H1N1, H2N2, H3N2). Recent appearances of H5N1, H6N1, H7N7, H7N9, H9N2, and H10N8 in humans are constant reminders of the potential for devastating new pandemics. Influenza B viruses with its two lineages further increase the health and economic burdens of seasonal influenza. No effective antiviral drugs are currently available for preventing entry of influenza A or B viruses into host cells (scientific premise). However, relatively recent discoveries of broadly neutralizing antibodies to human influenza viruses and concomitant structural studies have identified sites-of-vulnerability on the HA in pandemic, seasonal, and emerging influenza viruses. These HA surface sites include the receptor binding site and membrane-proximal stem housing the fusion machinery, both of which are essential for cellular infection. Common features for recognition of these sites can now be exploited in design of small molecules to ultimately develop broadly applicable influenza antivirals. Here, we will employ this structural information into the optimization and execution of high-throughput assays to identify new small-molecule scaffolds that target the highly conserved and vulnerable stem-binding site. High- throughput screening will be performed in parallel on representative HAs from influenza A group 1 against 600K structurally diverse molecules (SA1). We will also subject group 2 and influenza B HAs to a 300K compound screen (SA2). Validated hit compounds will be prioritized based on affinity and breadth across HAs and top candidates will be rigorously optimized into lead molecules by x-ray structure-based design cycled with medicinal chemistry. Biophysical binding, cellular infectivity and resistance assays (e.g., combinatorial viral libraries of HA mutants) will aid in iterative design, selection, and characterization of potential novel therapeutic candidates with favorable drug-like properties. All of these methods are actively employed in the Wolan and Wilson laboratories. As proof-of-concept for this approach, we identified a molecule with modest affinity to the stem of group 1 HAs with an HT assay of our own design. Its co-crystal structure with HA provided critical information towards design and synthesis of a focused compound library, which we used to produce a stereoselective molecule with nanomolar affinity and antiviral activity. Our overall goal is to identify and improve molecules with broad potency against the stem of groups 1 and 2 as well as flu B HAs. To our knowledge, we are the first to design an assay against group 2 and flu B HAs amenable to HTS (innovation). We anticipate that several classes of stem-targeted compound scaffolds will be identified with nanomolar affinity to HAs with cellular antiviral activity and suitable PK-ADME properties. Future efforts will include animal models of influenza infections to further validate our antivirals with the ultimate goal of combatting future influenza pandemics and seasonal epidemics.


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: 2024 ( Subtotal = $691,905 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	4/9/2024	NON-COMPETING CONTINUATION	$691,905
														Subtotal = $691,905

Issue Date FY: 2023 ( Subtotal = $678,526 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	4/19/2023	NON-COMPETING CONTINUATION	$678,526
														Subtotal = $678,526

Issue Date FY: 2022 ( Subtotal = $678,526 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	4/22/2022	NON-COMPETING CONTINUATION	$678,526
														Subtotal = $678,526

Issue Date FY: 2021 ( Subtotal = $678,526 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	4/26/2021	NEW	$678,526
														Subtotal = $678,526

Grand Total All Awards = $2,727,483

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High-throughput assays and small-molecule discovery of antiviral candidates targeting influenza hemagglutinin

Award Number: R01AI150885

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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