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Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease

Award Number: R21AI159740
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: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease - Project Summary Emerging viral infections caused by mosquito-borne alphaviruses such as Venezuelan/West- ern/Eastern equine encephalitis virus (VEEV, EEEV or WEEV) and Chikungunya virus are loom- ing threats to public health systems around the world. There are no vaccines or therapeutics ap- proved for human use against alphaviruses, and we have limited understanding of the molecular pathogenicity of most alphaviruses. If regional or transnational outbreak of alphavirus infections occur in the future, loss of life and loss of economic productivity can be minimized or prevented if therapeutic or prophylactic agents are available. In this application, we propose an investiga- tion into a new series of molecules that inhibit the protease domain of the non-structural protein 2 (nsP2) of VEEV, blocks the replication of VEEV in human cells, and are amenable to systematic structural changes that is important for drug development. The main goals of this project are: (a). To investigate covalent and mechanism-based reversible inhibitors of nsP2 using multiparameter structure-activity studies relationships (SAR) studies along with complementary metabolic and bioavailability studies; and (b). To investigate the molecular interactions between the molecules and nsP2 using crystallography and molecular modelling, which will facilitate target-specific op- timization of drug lead candidates. The project goals will facilitate the advancement of the com- pound series towards preclinical investigation as first-in-class nsP2 inhibitors that have anti-al- phaviral activities at physiologically relevant concentrations. Additionally, the molecules will also serve as valuable molecular tools to advance our understanding of the role of nsP2 in the pathogenicity of alphaviruses.


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 = -$66,303 )
2025	2022	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	001	2	2/13/2025	SUPPLEMENT FOR EXPANSION	-$39,250
2025	2022	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	000	2	2/13/2025	NON-COMPETING CONTINUATION	-$27,053
														Subtotal = -$66,303

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	000	2	10/18/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	000	2	8/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $437,700 )
2022	2022	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST STE 206	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	001	2	8/31/2022	SUPPLEMENT FOR EXPANSION	$259,110
2022	2022	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST STE 206	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	000	2	7/21/2022	NON-COMPETING CONTINUATION	$178,590
														Subtotal = $437,700

Issue Date FY: 2021 ( Subtotal = $182,090 )
2021	2021	JACKSON STATE UNIVERSITY	1400 J R LYNCH ST STE 206	JACKSON	MS	39217	HINDS	USA	Allergy and Infectious Diseases Research	000	1	8/27/2021	NEW	$182,090
														Subtotal = $182,090

Grand Total All Awards = $553,487

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Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease

Award Number: R21AI159740

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: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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