Tuesday, November 4, 2025 11/4/2025

Identification of targets of the antiparasitic drug praziquantel

Award Number: R01AI145871
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Identification of targets of the antiparasitic drug praziquantel - PROJECT SUMMARY The parasitic infection schistosomiasis afflicts over 200 million people worldwide and is clinically treated using a single drug, praziquantel (±PZQ). Although ±PZQ has served as a stalwart anthelmintic for decades, the molecular basis of action of this drug remains undefined. This lack of mechanistic knowledge impedes rational design of alternative therapeutics and is worrisome in the face of emergence of schistosome strains exhibiting refractoriness to ±PZQ exposure given ±PZQ is ineffective against all parasitic life cycle stages. Insight into the targets of ±PZQ action, and their effectors, is therefore needed to develop improved anthelmintic therapies. This R01 application is based around preliminary data supporting a premise that PZQ is a serotonin-like ligand in both the parasite and the human host. Our laboratory has recently identified targets for both R-PZQ and S- PZQ, the two enantiomers in the clinical formulation of ±PZQ. R-PZQ is a ligand at the human 5-HT2B G protein coupled receptor (5-HT2B GPCR), and S-PZQ is a serotonergic regulator of the human transient receptor potential melastatin 8 ion channel (TRPM8). These findings are significant as they (i) provide clues to the likely targets of PZQ enantiomers in the parasite (5-HT GPCRs & TRP channels) and (ii) demonstrate that PZQ does not act as a selective antiparasitic, but also is active in the host. Notably ±PZQ acutely changes blood vessel tone within the mesenteric blood vessels where the adult worms reside. Chronic engagement of 5-HT GPCRs in hepatic stellate cells inhibited fibrotic changes caused by inflammatory reactions to worm eggs deposited in host tissues. Coalescing such beneficial host and deleterious parasitic activities provides a novel route to generating improved antiparasitic therapies that kill worms and prevent the tissue damage they cause. Based on our discoveries, we will map the binding sites of R-PZQ on 5-HT2BR, and S-PZQ on TRPM8 and use these binding poses to identify similar binding architectures in schistosome bioaminergic GPCRs (Aim 1) and TRP channels (Aim 2). Following this strategy, we have recently identified a schistosome TRP channel that is regulated by PZQ (10) – the first target of PZQ ever identified in a flatworm. Finally, we will address the clinical significance of host bioactivity of anthelmintics (Aim 3) in terms of acute effects on the vasculature, and chronic effects on hepatic stellate cells that initiate fibrogenic changes underpinning many of the pathologies of chronic schistosomiasis. Our collaborative team bring together expertise in 5-HT2B receptor structure, TRP channel biology and blood vessel physiology to execute activities from molecular (receptor structure) to in vivo pathology (mechanisms regulating parasite infection and liver disease). If successful, our activities will resolve targets and effectors for ±PZQ that will enable development of better anthelmintic therapies and adjuncts.


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 = $181,268 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	6	1/14/2025	COMPETING CONTINUATION	$524,160
2025	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	5	7/18/2025	NON-COMPETING CONTINUATION	-$342,892
														Subtotal = $181,268

Issue Date FY: 2024 ( Subtotal = $444,538 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	5	3/15/2024	NON-COMPETING CONTINUATION	$444,538
														Subtotal = $444,538

Issue Date FY: 2023 ( Subtotal = $444,538 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	4	3/3/2023	NON-COMPETING CONTINUATION	$444,538
														Subtotal = $444,538

Issue Date FY: 2022 ( Subtotal = $444,538 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	3	3/15/2022	NON-COMPETING CONTINUATION	$444,538
														Subtotal = $444,538

Issue Date FY: 2021 ( Subtotal = $657,093 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	001	2	3/11/2021	NON-COMPETING CONTINUATION	$444,538
2021	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	1	1/21/2021	NEW	$212,555
														Subtotal = $657,093

Issue Date FY: 2020 ( Subtotal = $300,026 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Allergy and Infectious Diseases Research	000	1	3/16/2020	NEW	$300,026
														Subtotal = $300,026

Grand Total All Awards = $2,472,001

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Identification of targets of the antiparasitic drug praziquantel

Award Number: R01AI145871

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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