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Identification of a new drug target, sarco-endoplasmic reticulum calcium-ATPase, for the treatment of Toxoplasma gondii infections and development of a selective inhibitor.

Award Number: R21AI196143
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: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Identification of a new drug target, sarco-endoplasmic reticulum calcium-ATPase, for the treatment of Toxoplasma gondii infections and development of a selective inhibitor. - Project Summary The parasitic protozoan Toxoplasma gondii is a leading cause of infectious blindness globally, can cause severe birth defects or in utero demise in a developing fetus and lethal encephalitis in immune compromised patients. All medications in use against it are repurposed antimalarials that cannot completely eradicate the infection and must be taken for weeks to months yet frequently have toxic, treatment-limiting side effects. There is a clear need to identify new drug targets in T. gondii that will enable new, more effective, less toxic therapies. We have discovered a novel compound active that is against T. gondii in vitro (EC50 = 303 nM) and have preliminary evidence that its target is sarco-endoplasmic calcium-ATPase (SERCA), a calcium pump that plays a critical role in controlling the cytoplasmic calcium concentration of the parasite. Active transport of calcium by T. gondii SERCA (TgSERCA) enables rapid oscillations in cytoplasmic calcium (calcium signaling) that coordinate numerous essential activities in the lytic cycle of the parasite including invasion of host cells, egress from them, and gliding motility between them. Disrupting the function of TgSERCA with nonselective inhibitors is known to disrupt all of these processes simultaneously. A selective inhibitor of TgSERCA has the potential to be powerful new therapy for toxoplasmosis. IPS was discovered in the largest compound screen against T. gondii to date. T. gondii mutants resistant to IPS have mutations in TgSERCA and are cross- resistant to thapsigargin, a well-characterized inhibitor of diverse SERCAs. It is likely that SERCA is the target of IPS in T. gondii but there is currently no direct evidence demonstrating this. The ﬁrst part of this project will verify that TgSERCA is the target of IPS and describe the effects of IPS on the motility, invasion, and egress of T. gondii tachyzoites. We will model the binding of IPS to TgSERCA using computational methods and attempt the same with the human ortholog HsSERCA2a to describe a structural basis for selective binding. We will use an established yeast model to directly measure the inhibition of TgSERCA and HsSERCA2a by IPS. We will describe the effects of IPS on T. gondii cytoplasmic calcium concentrations, microneme secretion, invasion, gliding motility, and egress. IPS is rapidly degraded by mouse liver microsomes and due to this metabolic instability, is itself unlikely to be effective in treating toxoplasmosis. The second part of this project will determine the source of metabolic instability and use this information to synthesize metabolically stable IPS derivatives. We will describe the pharmacokinetics of the ﬁve most potent, stable derivatives in brain tissue and serum. The three derivatives with the most optimal time-concentration proﬁles will be tested in established mouse models of systemic and latent toxoplasmosis. These studies will verify the target of IPS and correct its metabolic liability, adding to our knowledge of drug targets in T. gondii and placing IPS in an excellent position for future drug development efforts.


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: 2026 ( Subtotal = $189,000 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	1	9/15/2026	NEW	$189,000
														Subtotal = $189,000

Grand Total All Awards = $189,000

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Identification of a new drug target, sarco-endoplasmic reticulum calcium-ATPase, for the treatment of Toxoplasma gondii infections and development of a selective inhibitor.

Award Number: R21AI196143

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: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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