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Characterizing and targeting malaria parasite purine uptake pathways to generate novel antimalarial drugs

Award Number: F31AI136488
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Abstract Malaria remains a major public health issue. Infection with Plasmodium falciparum species parasites is most lethal. Increasing resistance to current antimalarial treatments makes new drug development imperative. Plasmodium parasites are obligate intracellular purine auxotrophs. Purine salvage pathways are therefore good targets for antimalarial drug development. An equilibrative nucleoside transporter, PfENT1, is the primary pathway for purine uptake by P. falciparum. However, there has been evidence of a secondary pathway that can import AMP as a purine source. This pathway remains to be characterized. In Aim #1 I will characterize the AMP purine transport into P. falciparum through radiolabel substrate uptake inhibition experiments with purines and potential inhibitors. I will test whether AMP transport is mediated through a sodium-coupled or proton- coupled process. Results from these experiments will provide novel insight into P. falciparum biology. Previous work in the lab using a high throughput screen identified PfENT1 inhibitors. The hits block the transporter and kill malaria parasites in culture. However, these initial hits are not potent enough to be drugs. In Aim #2, I will participate in the hit-to-lead medicinal chemistry process to optimize these PfENT1 inhibitor hits and determine the structure-activity relationships for these compounds. I will evaluate their potency in parasite cytotoxicity assays and their human cell toxicity using human hepatoma HepG2 cytotoxicity assays. This process will allow us to determine what chemical characteristics provide drug hits with the potential to be converted into drug candidates. In Aim #3, I will determine whether naturally occurring non-synonymous single nucleotide polymorphisms (SNP) identified in genome sequencing of P. falciparum field isolates affect efficacy of the PfENT1 inhibitors that we are developing as potential antimalarial drugs. It is possible that the efficacy of PfENT1 inhibitors can be affected by the presence of SNPs in PfENT1. We have identified 13 non- synonymous SNPs in the more than 100 sequences in the PlasmoDB database. I will express PfENT1-SNPs in Saccharomyces cerevisiae by using a PfENT1-pCM189 yeast expression vector. I will determine whether the SNPs affect purine import and PfENT1 inhibitor efficacy. Available PfENT1-SNP expressing parasite isolates will also be tested using parasite cytotoxicity assays with inhibitors. These experiments will help us determine if PfENT1 SNPs could cause resistance to our inhibitors. These experiments will advance the drug development process for the PfENT1 inhibitors and hopefully lead to the development of successful antimalarial drugs. Participation in this project will provide me with the opportunity to learn about membrane transport physiology, parasite biology and the early stage drug development process. It will provide me with an excellent foundation for a career in biomedical research.


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 = -$2,341 )
2022	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	004	4	4/22/2022	NON-COMPETING CONTINUATION	-$2,341
2022	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	4	4/22/2022	NON-COMPETING CONTINUATION	$0
2022	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	3	4/22/2022	NON-COMPETING CONTINUATION	$0
2022	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	2	4/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	4/22/2022	NEW	$0
														Subtotal = -$2,341

Issue Date FY: 2021 ( Subtotal = -$12,375 )
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	4	10/16/2020	NON-COMPETING CONTINUATION	-$12,375
														Subtotal = -$12,375

Issue Date FY: 2020 ( Subtotal = $45,520 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	4	9/16/2020	NON-COMPETING CONTINUATION	$0
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	4	1/6/2020	NON-COMPETING CONTINUATION	$45,016
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	4	3/6/2020	NON-COMPETING CONTINUATION	$504
														Subtotal = $45,520

Issue Date FY: 2019 ( Subtotal = $45,016 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	3	3/22/2019	NON-COMPETING CONTINUATION	$45,016
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	2/8/2019	NEW	-$5,121
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	2	2/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$5,121
														Subtotal = $45,016

Issue Date FY: 2018 ( Subtotal = $44,524 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	1/24/2018	NEW	$44,044
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	1	5/21/2018	NEW	$480
														Subtotal = $44,524

Grand Total All Awards = $120,344

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Characterizing and targeting malaria parasite purine uptake pathways to generate novel antimalarial drugs

Award Number: F31AI136488

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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