Tuesday, July 1, 2025 7/1/2025

Development of NLRP3 inhibitors for HIV-associated neuroinflammation

Award Number: R21NS129478
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Development of NLRP3 inhibitors for HIV-associated neuroinflammation - ABSTRACT The advent of effective combination antiretroviral therapies (cART) has increased the life expectancy for HIV-1 patients, however, these patients are still prone to comorbidities, such as HIV-associatiated neurocognitive disorders (HAND), which affect up to 50% of HIV-infected individuals. Persistent inflammation due to the overactivation of the innate immune system is one of the main underlying causes of HAND. Nucleotide binding domain, leucine rich repeat pyrin domain containing protein-3 (NLRP3) inflammasome has emerged as a druggable target for the management of HIV-1-associated neuropathologies. The NLRP3 inflammasome is shown to be activated in response to a wide array of pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively). A key step in the activation process is a homotypic interaction between the pyrin domains in NLRP3 and an adapter protein, apoptosis-associated speck-like protein containing a CARD (ASC). NLRP3 activation leads to the release of pro-inflammatory cytokines, such as, interleukin-1 (IL-1) and IL-18, causing neuronal pyroptosis and death. Disruption of NLRP3 signaling via small molecules, such as MCC950, is reported to display beneficial effects in the transgenic mouse models. Our recent studies identified a small molecule, AMS-17, that thwarted the NLRP3 activation in N9 microglia both in vitro and in vivo. Subsequent mechanistic analysis revealed that the NLRP3 inhibitory activity of AMS-17 is attributed to its ability to bind to NLRP3 pyrin domain, thus preventing the interaction between NLRP3 and ASC. This proposal is focused on developing AMS-17 analogues with improved biological activity, low toxicity, and high drug-likeness. Aim 1 described in this proposal is focused on the computer-assisted design, synthesis and chemical characterization of AMS-17 analogues. Aim 2 will involve testing of the lead candidates in the humanized mouse model of HAND. The proposed studies are highly significant since they will provide new therapeutic options to minimize HIV-associated neurocognitive dysfunction. The proposal incorporates expertise in the area of synthetic medicinal chemistry (Dr. Kulkarni), biological screening (Dr. Bukrinsky), and computer-assisted drug design (Dr. Adzhubei). It is fully consistent with the goals of this RFA and is expected to define NLRP3 inhibitory compounds working through a novel mechanism different from that of any other currently used drug.


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 = $245,759 )
2025	2023	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	10/22/2024	NON-COMPETING CONTINUATION	-$156,884
2025	2023	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	2	11/1/2024	NON-COMPETING CONTINUATION	-$79,242
2025	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	3	11/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,875
2025	2023	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	10/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$156,884
2025	2023	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	10/16/2024	NON-COMPETING CONTINUATION	$236,126
2025	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	10/16/2024	NEW	$9,633
2025	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	1	11/1/2024	NEW	-$9,633
														Subtotal = $245,759

Issue Date FY: 2024 ( Subtotal = -$245,759 )
2024	2023	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/17/2024	NON-COMPETING CONTINUATION	-$236,126
2024	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2024	NEW	-$9,633
														Subtotal = -$245,759

Issue Date FY: 2023 ( Subtotal = $236,126 )
2023	2023	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/13/2023	NON-COMPETING CONTINUATION	$236,126
														Subtotal = $236,126

Issue Date FY: 2022 ( Subtotal = $212,000 )
2022	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/21/2022	NEW	$212,000
														Subtotal = $212,000

Grand Total All Awards = $448,126

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Development of NLRP3 inhibitors for HIV-associated neuroinflammation

Award Number: R21NS129478

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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