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Large-scale screen with a novel assay against RNA editing to identify anti-trypanosomal agents

Award Number: R01AI143593
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: 03/06/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Large-scale screen with a novel assay against RNA editing to identify anti-trypanosomal agents - PROJECT SUMMARY / ABSTRACT This project will target the essential RNA editing multi-protein complex (the editosome) in related trypanosomatid pathogens (Trypanosoma brucei, T. cruzi, and Leishmania spp.), which are the causative agents of African sleeping sickness, Chagas' disease, and leishmaniasis, respectively. It will identify inhibitors of this essential process, utilizing the capacity of a FRET-based assay for a sensitive “mix and measure” in vitro monitoring of RNA editing activity in T. brucei, which we developed in a previous R21 assay development grant. Our preliminary data show that the editosomes are highly conserved among trypanosomatids; these data suggest the important possibility that inhibitors found against T. brucei editosome proteins will also be effective against the editosome in related trypanosomatid pathogens (T. cruzi and Leishmania spp.). To address the assay feasibility, we completed a pilot screen of the library of pharmacologically active compounds (LOPAC1280) and discovered new inhibitors that specifically interfere with RNA editing and kill T. brucei in vitro. Motivated by these recent experiments, we propose to screen a large library of compounds against the editosome in collaboration with Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys Medical Discovery Institute. In Aim 1, editosomes and RNAs will be prepared, while we further miniaturize to 1536-well the 384-well RNA editing assay, and implement it in an HTS campaign. Aim 2 will confirm RNA editing inhibitors and determine their potency (IC50), and will assess growth inhibition of the bloodstream forms of T. brucei. Aim 3 will elucidate the nascent structure-activity relationships (SAR) of chemical scaffolds and optimize the selected hits to improve target specificity and potency of inhibitors. It will then investigate the MOA and cross-species effect of the best inhibitory compound(s), followed by scale-up to benchmark their ADME/T & PK properties. These inhibitory compound(s) will provide well-characterized chemical tool(s) or probe(s) to dissect the dynamic assembly of the editosome proteins and preferential targets that may serve as new therapeutic scaffolds against trypanosomatid pathogens.


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: 2024 ( Subtotal = $0 )
2024	2021	THE ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING	845 ST SHERBROOKE W	MONTREAL	QC			CAN	Allergy and Infectious Diseases Research	000	3	1/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $362,540 )
2021	2021	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ			CAN	Allergy and Infectious Diseases Research	000	3	3/9/2021	NON-COMPETING CONTINUATION	$362,540
														Subtotal = $362,540

Issue Date FY: 2020 ( Subtotal = $430,672 )
2020	2020	ROYAL INSTITUTION FOR THE ADVANCEMENT OF LEARNING / MCGILL	845 RUE SHERBROOKE O	MONTREAL	PQ	H3A 0G4		CAN	Allergy and Infectious Diseases Research	000	2	1/30/2020	NON-COMPETING CONTINUATION	$430,672
														Subtotal = $430,672

Issue Date FY: 2019 ( Subtotal = $556,320 )
2019	2019	ROYAL INSTITUTE FOR ADVANCEMENT OF LEARNING MCGILL	845 SHERBROOKE STREET WEST	MONTREAL	PQ	H3A 0G4		CAN	Allergy and Infectious Diseases Research	000	1	3/6/2019	NEW	$556,320
														Subtotal = $556,320

Grand Total All Awards = $1,349,532

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Large-scale screen with a novel assay against RNA editing to identify anti-trypanosomal agents

Award Number: R01AI143593

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: 03/06/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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