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Development of 2C inhibitors as broad-spectrum enterovirus antivirals

Award Number: R01AI179926
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: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Development of 2C inhibitors as broad-spectrum enterovirus antivirals - Project Summary Non-polio enteroviruses (NPEVs) are etiological agents for several human diseases including respiratory infections, hand-foot-and-mouth disease (HFMD), aseptic meningitis, encephalitis, neonatal sepsis, myocarditis, conjunctivitis, and acute flaccid paralysis. Among the more than 100 serotypes of NPEVs, some of the most significant pathogens are enterovirus D68 (EV-D68), enterovirus A71 (EV-A71) and coxsackievirus B3 (CV-B3). According to CDC, these NPEVs combined have caused 10 to 15 million infections and tens of thousands of hospitalizations in the U.S. Clearly, NPEVs are a public concern for both U.S. and the world. No vaccines are available in the U.S. for the NPEVs such as EV-D68, EV-A71, and CV-B3. Three inactivated EV-A71 vaccines are available in China. However, there are not broadly protective, and the efficacy is limited to certain strains. There is no FDA-approved antiviral for any of these NPEVs. Thus, there is a pressing need to develop orally bioavailable pan-enterovirus antivirals. This proposal focuses on targeting the enterovirus nonstructural 2C protein for the development of orally bioavailable broad-spectrum NPEV antivirals. Specifically, in Aim 1, we will optimize the antiviral activity and pharmacokinetic properties of three series of 2C inhibitors. In Aim 2, we will determine the high-resolution X- ray crystal structures of EV-A71, EV-D68, and CV-B3 2C proteins with structurally disparate 2C inhibitors. In Aim 3, we will evaluate the in vivo antiviral efficacy of 2C inhibitors in EV-D68 and EV-A71 infection mouse models. Successful implementation of this proposal will provide orally bioavailable broad-spectrum NPEV drug candidates for further development.


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: 2026 ( Subtotal = $768,200 )
2026	2026	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	3	12/19/2025	NON-COMPETING CONTINUATION	$768,200
														Subtotal = $768,200

Issue Date FY: 2025 ( Subtotal = $740,419 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	1/8/2025	NON-COMPETING CONTINUATION	$740,419
														Subtotal = $740,419

Issue Date FY: 2024 ( Subtotal = $755,280 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$74,103
2024	2024	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	11/22/2023	NEW	$681,177
														Subtotal = $755,280

Grand Total All Awards = $2,263,899

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Development of 2C inhibitors as broad-spectrum enterovirus antivirals

Award Number: R01AI179926

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: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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