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The Function of Antimalarial Drug Resistance Proteins

Award Number: R01AI056312
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: 06/15/2003
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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The Function of Antimalarial Drug Resistance Proteins - Project Summary Malarial parasite sensitivity to chloroquine (CQ) as well as important artemisinin combination therapy (ACT) partner drugs (notably piperaquine [PPQ], amodiaquine [AQ], and lumefantrine [LF]) and are affected by mutations in the P. falciparum transporter PfCRT. Of the 61 known distinct PfCRT protein isoforms discovered since 2000, some mediate emerging or evolving phenotypes selected for by relatively recent changes in front- line antimalarial drug therapy. In drug resistant parasites, PfCRT protein harbors 4 to 10 amino acid substitutions relative to wild type. These confer most of the ~ 10-fold shift in CQ IC50 seen for common CQ- resistant (CQR) strains, with milder, variable resistance to other drugs often observed in these strains. However, only a handful of the isoforms have been studied in molecular depth. The Dd2 (Asia/Africa) and 7G8 (S. America) isoforms both confer CQR, but 7G8 PfCRT confers lower CQR and also mediates AQR. Recent data shows some rare mutant PfCRTs may not confer drug resistance at all. This project brings together expertise in protein biochemistry, transporter physiology, reverse genetics, and structural biology by leveraging the established expertise of the Roepe (Georgetown), Fidock (Columbia), Chang (UCSD), and Stowell (U.C.,Boulder) laboratories to comprehensively define how new mutant isoforms of PfCRT influence currently evolving antimalarial drug resistance. We have three aims: 1) we will use novel and previously validated antimalarial drug probes, engineered yeast strains and purified recombinant protein to unambiguously define function of PfCRT isoforms expressed in evolving P. falciparum resistant to both quinoline – based (chloroquine; CQ, piperaquine; PPQ) and Artemisinin – based drugs, 2) we will characterize reverse engineered strains of P. falciparum expressing PfCRT isoforms that are created in specific P. falciparum genetic backgrounds, in order to isolate and characterize the precise contribution of PPQR-associated PfCRT function to evolving phenotypes, and 3) we will leverage our considerable progress with purification of PfCRT, highthroughput production of PfCRT specific nanobodies, cryoEM methods, molecular dynamics, and other physical chemical approaches to significantly expand recent collaborative success at defining atomic level structure of PfCRT isoforms.


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 = $483,707 )
2025	2025	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	18	10/30/2024	NON-COMPETING CONTINUATION	$483,707
														Subtotal = $483,707

Issue Date FY: 2024 ( Subtotal = $490,389 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	17	11/1/2023	NON-COMPETING CONTINUATION	$441,351
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	17	5/14/2024	NON-COMPETING CONTINUATION	$49,038
														Subtotal = $490,389

Issue Date FY: 2023 ( Subtotal = $340,779 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	16	10/27/2022	NON-COMPETING CONTINUATION	$497,172
2023	2020	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	14	3/9/2023	NON-COMPETING CONTINUATION	-$156,393
														Subtotal = $340,779

Issue Date FY: 2022 ( Subtotal = $545,387 )
2022	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	002	15	9/13/2022	COMPETING CONTINUATION	$0
2022	2022	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	15	10/26/2021	COMPETING CONTINUATION	$545,387
2022	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	14	10/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $545,387

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	GEORGETOWN UNIVERSITY (THE)	37TH AND O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	14	3/15/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $413,757 )
2020	2020	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	14	11/21/2019	NON-COMPETING CONTINUATION	$413,757
														Subtotal = $413,757

Issue Date FY: 2019 ( Subtotal = $413,757 )
2019	2019	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	13	11/7/2018	NON-COMPETING CONTINUATION	$413,757
														Subtotal = $413,757

Issue Date FY: 2018 ( Subtotal = $413,757 )
2018	2018	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	12	11/24/2017	NON-COMPETING CONTINUATION	$413,757
														Subtotal = $413,757

Issue Date FY: 2017 ( Subtotal = $413,757 )
2017	2017	GEORGETOWN UNIVERSITY (THE)	37TH & O STS NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	11	11/23/2016	NON-COMPETING CONTINUATION	$413,757
2017	2016	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	002	10	5/24/2017	COMPETING CONTINUATION	$9,874
2017	2012	GEORGETOWN UNIVERSITY (THE)	37TH & O ST NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	001	9	5/24/2017	NON-COMPETING CONTINUATION	-$9,874
														Subtotal = $413,757

Issue Date FY: 2016 ( Subtotal = $448,705 )
2016	2016	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	10	11/25/2015	COMPETING CONTINUATION	$448,705
														Subtotal = $448,705

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	9	4/24/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $338,503 )
2012	2012	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	9	5/15/2012	NON-COMPETING CONTINUATION	$338,503
														Subtotal = $338,503

Issue Date FY: 2011 ( Subtotal = $338,503 )
2011	2011	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	8	6/3/2011	NON-COMPETING CONTINUATION	$338,503
														Subtotal = $338,503

Issue Date FY: 2010 ( Subtotal = $341,921 )
2010	2010	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	7	5/14/2010	NON-COMPETING CONTINUATION	$341,921
														Subtotal = $341,921

Issue Date FY: 2009 ( Subtotal = $491,200 )
2009	2009	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Trans-NIH Recovery Act Research Support	001	6	9/7/2009	SUPPLEMENT FOR EXPANSION	$145,825
2009	2009	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	6	8/4/2009	NON-COMPETING CONTINUATION	$345,375
														Subtotal = $491,200

Issue Date FY: 2008 ( Subtotal = $370,375 )
2008	2008	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	5	5/19/2008	COMPETING CONTINUATION	$370,375
														Subtotal = $370,375

Issue Date FY: 2006 ( Subtotal = $303,106 )
2006	2006	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Allergy and Infectious Diseases Research	000	4	11/30/2005	NON-COMPETING CONTINUATION	$303,106
														Subtotal = $303,106

Issue Date FY: 2005 ( Subtotal = $310,400 )
2005	2005	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Microbiology and Infectious Diseases Research	000	3	12/3/2004	NON-COMPETING CONTINUATION	$310,400
														Subtotal = $310,400

Issue Date FY: 2004 ( Subtotal = $310,400 )
2004	2004	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Microbiology and Infectious Diseases Research	000	2	12/19/2003	NON-COMPETING CONTINUATION	$310,400
														Subtotal = $310,400

Issue Date FY: 2003 ( Subtotal = $145,540 )
2003	2003	GEORGETOWN UNIVERSITY	37TH & O STREETS, NW	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Microbiology and Infectious Diseases Research	000	1	6/3/2003	NEW	$145,540
														Subtotal = $145,540

Grand Total All Awards = $6,913,943

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The Function of Antimalarial Drug Resistance Proteins

Award Number: R01AI056312

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: 06/15/2003

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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