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Protein kinase AEK1 as a T. brucei drug target and its potential in other trypanosomatids

Award Number: R21AI130685
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: 05/08/2018
PERIOD OF PERFORMANCE END DATE: 09/30/2018

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Protein kinase AEK1 as a T. brucei drug target and its potential in other trypanosomatids - ABSTRACT Trypanosomatid parasites cause some of the most challenging neglected diseases worldwide. The human- pathogenic triumvirate of Trypanosoma brucei spp., Trypanosome cruzi, and Leishmania spp. sickening hundreds of thousands of individuals, causing human African trypanosomiasis, Chagas' disease, and a range of visceral to cutaneous lesions, respectively. However, there are no approved vaccines and treatments are difficult due to side-effects, resistance, and regimens that are unsuitable for resource-limited settings. Therefore, discovery of new drugs is critical for therapy, control, and elimination of these diseases. We have recently shown that the protein kinase, AEK1, which is both highly conserved in these agents yet different from human protein kinases, is essential in the pathogenic bloodstream stage of T. brucei in vitro. We have also chemically validated it as important during infection. To discover T. brucei AEK1 inhibitors we will screen well- curated, focused kinase libraries against the purified enzyme, counterscreening against the closest human paralog, with subsequent testing of compounds on cultured bloodstream stage T. brucei. Such compounds will serve as a starting point for future work to develop drugs for treatment and eradication of human African trypanosomiasis. Surprisingly, few drug targets have been validated across pathogenic trypanosomatid species, despite their closely related proteomes. Therefore, we will test whether AEK1 could serve as a pan- trypanosomatid drug target by determining whether it is essential in the pathogenic stages of Leishmania donovani, and through collaboration, T. cruzi. If so, we will quantify activity of the discovered inhibitors against the L. donovani and T. cruzi enzymes and against L. donovani amastigotes. The results will inform us as to whether AEK1 is a suitable drug target for multiple parasite species, which would leverage future medicinal chemistry aimed at enhancing selectivity, efficacy and bioavailability of compounds identified in this 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: 2022 ( Subtotal = $0 )
2022	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	3	11/22/2021	NON-COMPETING CONTINUATION	$0
2022	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	9/26/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	3	6/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $229,520 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	004	3	3/27/2019	NON-COMPETING CONTINUATION	$238,806
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	2	11/30/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$236,354
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	005	1	7/23/2019	NEW	$0
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	1	1/10/2019	NEW	-$1
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	11/30/2018	NEW	-$236,354
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	2	1/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$9,285
														Subtotal = $229,520

Issue Date FY: 2018 ( Subtotal = $304,862 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	5/7/2018	NEW	$304,862
														Subtotal = $304,862

Grand Total All Awards = $534,382

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Protein kinase AEK1 as a T. brucei drug target and its potential in other trypanosomatids

Award Number: R21AI130685

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: 05/08/2018

PERIOD OF PERFORMANCE END DATE: 09/30/2018

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