Monday, June 30, 2025 6/30/2025

Plasmodium Protein Kinase Focused Antimalarials Discovery

Award Number: R01AI172066
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: 07/11/2022
PERIOD OF PERFORMANCE END DATE: 03/11/2025

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Plasmodium Protein Kinase Focused Antimalarials Discovery - Malaria still afflicts about half of the world population causing more than 400,000 deaths, mostly children. It is quite alarming that the options for malaria therapy are increasingly becoming limited because of widespread drug resistance. Furthermore, most of the antimalarials act only on the erythrocytic stages, the drugs for prophylaxis and relapse of malaria are suboptimal. To address the fragility of malaria therapy, we propose to discover and optimize next generation antimalarials acting on underexplored Plasmodium kinases. We will leverage wealth of knowledge on diverse chemical scaffolds and know-how related to the drug development and tolerability of kinase inhibitor-based therapies for various human diseases. We will focus on type II kinase inhibitors that have been designed to overcome selectivity issues by using both the ATP-binding site as well as the adjacent hydrophobic region created by the activation loop in the inactive conformation. To the best of our knowledge, type II inhibitors are yet to be explored as antimalarial agents. Premise for this proposal is based on our promising preliminary screening that has identified type II compounds with therapeutic and prophylactic activities. The goal of this project is to test the hypothesis that we can design effective type II chemical scaffolds that act on multiple stages of parasite development. To achieve this goal, we propose to pursue the following: (1) Design and synthesize optimized selective antimalarial type II compounds for in vivo application; antiplasmodial hits will be optimized to improve potency, selectivity, and pharmacological properties through stages of iterative analog design, synthesis, and evaluation of biological and biochemical activities. (2) Determine rate of killing, resistance profile, stage susceptibility, and efficacy of lead compounds in murine and humanized mouse models. Furthermore, the ability of the lead compounds to inhibit liver stage infection and gametocyte maturation will be assessed. 3) We will identify targets of antimalarial chemotypes using in vitro evolution of resistance followed by whole genome sequencing. We will use conditional knockdown and copy number variation of the resistance determinants for target validation. We will conduct phosphoproteomics analysis to uncover signaling pathways modulated by the type II inhibitors under study. The research in this endeavor will be conducted through a multidisciplinary collaboration between the laboratories of Debopam Chakrabarti (University of Central Florida), Nathanael Gray (Stanford University), Elizabeth Winzeler (University of California San Diego) with combined expertise in medicinal chemistry, kinase chemical biology, malaria cell biology, anti-infective discovery, target identification, and validation. Successful completion of these goal will lead to the discovery of novel chemical leads with therapeutic and prophylactic potential.


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 = -$11,846 )
2025	2024	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	3/31/2025	SUPPLEMENT FOR EXPANSION	-$11,846
														Subtotal = -$11,846

Issue Date FY: 2024 ( Subtotal = $830,216 )
2024	2024	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	002	3	6/21/2024	SUPPLEMENT FOR EXPANSION	$58,225
2024	2024	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	001	3	6/19/2024	NON-COMPETING CONTINUATION	$762,579
2024	2024	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	5/23/2024	SUPPLEMENT FOR EXPANSION	$9,412
														Subtotal = $830,216

Issue Date FY: 2023 ( Subtotal = $769,003 )
2023	2023	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	6/22/2023	NON-COMPETING CONTINUATION	$769,003
														Subtotal = $769,003

Issue Date FY: 2022 ( Subtotal = $801,255 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	7/11/2022	NEW	$801,255
														Subtotal = $801,255

Grand Total All Awards = $2,388,628

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Plasmodium Protein Kinase Focused Antimalarials Discovery

Award Number: R01AI172066

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: 07/11/2022

PERIOD OF PERFORMANCE END DATE: 03/11/2025

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