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Development of phenolic small molecule inhibitors of PfATP6, a Plasmodium calcium ATPase

Award Number: R16GM145435
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Development of phenolic small molecule inhibitors of PfATP6, a Plasmodium calcium ATPase - Project Summary/Abstract Malaria, an infectious disease caused by Plasmodium parasites, continues to pose a serious global health problem. PfATP6, a calcium-transporting enzyme present in Plasmodium falciparum, has been identified as a target for new antimalarial drugs. Therefore, specific and potent inhibitors of PfATP6 hold promise as a new generation of antimalarial agents. They may also be of value as research tools for the elucidation of the enzyme’s physiological roles. Only a few PfATP6 inhibitors are presently known and most of them suffer from limitations due to their high structural complexity, restricting their availability. A notable exception is a group of structurally simple phenolic compounds that were originally identified in library screens. As they feature hydroquinone and naphthoquinone scaffolds, they can be synthesized straightforwardly, which is a major advantage. The proposed project focusses on the design and characterization of novel PfATP6 inhibitors, with initial focus on the hydroquinone/naphthoquinone scaffolds. The long term goal of this research is to obtain a comprehensive understanding of the interactions between PfATP6 and small inhibitory molecules at the molecular level. As a first step, the objective of this proposal is to identify and characterize inhibitors that are good candidates for future development. Preliminary data suggest that the development of new PfATP6 inhibitors based on the targeted scaffolds is an achievable goal. To reach it, the following two Specific Aims will be pursued: Aim 1: Establish the structural requirements for effective PfATP6 inhibition. An initial library of 50-60 potential inhibitors will be obtained from vendors or be synthesized. These compounds will first be evaluated in inhibition assays with purified PfATP6 and then in viability assays with living parasites. The results will furnish structure-activity relationships that identify structural elements critical for inhibition. Aim 2: Identify novel inhibitor scaffolds using structural models of the inhibitor binding site of PfATP6. Applying computational techniques, structural models of the currently unknown inhibitor binding site will be generated. After having validated the models, their predictive capabilities will be employed for virtual screens of compound libraries to identify alternative inhibitor types. The ultimate goal is to increase the structural variety of the PfATP6 inhibitor pool by adding compounds with new scaffolds. The proposed research is innovative because it will be the first to systematically explore small molecule PfATP6 inhibitors by a combination of experimental and computational approaches. It is significant as it provides fundamental information necessary to develop novel anti-malarial agents and valuable new research tools. Moreover, the project will enable the PI to initiate and sustain a meritorious research program at Sacramento State, engaging students interested in a future career in biomedicine in a multi-disciplinary drug design project.


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 = $142,000 )
2025	2025	UNIVERSITY ENTERPRISES, INC.	6000 J ST STE 3700	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	3	5/2/2025	NON-COMPETING CONTINUATION	$142,000
														Subtotal = $142,000

Issue Date FY: 2024 ( Subtotal = $218,201 )
2024	2024	UNIVERSITY ENTERPRISES, INC.	6000 J ST STE 3700	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	001	2	6/19/2024	SUPPLEMENT FOR EXPANSION	$76,201
2024	2024	UNIVERSITY ENTERPRISES, INC.	6000 J ST STE 3700	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	2	5/17/2024	NON-COMPETING CONTINUATION	$142,000
														Subtotal = $218,201

Issue Date FY: 2023 ( Subtotal = $142,000 )
2023	2023	UNIVERSITY ENTERPRISES INC	6000 J ST	SACRAMENTO	CA	95819	SACRAMENTO	USA	Biomedical Research and Research Training	000	1	4/27/2023	NEW	$142,000
														Subtotal = $142,000

Grand Total All Awards = $502,201

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Development of phenolic small molecule inhibitors of PfATP6, a Plasmodium calcium ATPase

Award Number: R16GM145435

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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