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Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease

Award Number: R01AI154943
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT There are no effective therapies to treat Cryptosporidium, a waterborne parasite that is now recognized as significant cause of diarrheal disease worldwide and an important AIDS defining pathogen. In the process of mining compounds produced by marine symbiotic bacteria for anti-parasitic activity, we identified a compound, tartrolon E (trtE) that potently inhibits in vitro growth of Cryptosporidium parvum, as well as several other apicomplexan parasites, without toxicity to their respective host cells. We further established that trtE is highly effective at reducing Cryptosporidium infection in neonatal mice. In fact, trtE is 10-fold more effective in vitro and 2-fold more effective in vivo against Cryptosporidium than the most effective compounds reported to date, and the only compound to hold the promise of a broad spectrum anti-apicomplexan therapeutic. These observations strongly encourage further exploration of the clinical potential of trtE for the treatment of cryptosporidiosis. In the studies proposed here, we will test the hypothesis that trtE possesses the activity necessary to be lead candidate therapeutic for the treatment of cryptosporidiosis by completion of the following aims: Aim 1: To evaluate species specificity and life cycle stage specificity of trtE against Cryptosporidium. TrtE will be tested against C. parvum field isolates and C. hominis and the activity of trtE against oocysts, sporozoites, asexual and sexual stages will be determined. Aim 2: To optimize trtE dosing regimens. Pharmacodynamics (A), pharmacokinetics (B) and bioavailability (C) studies will be conducted to design optimal treatment strategies. Aim 3: To evaluate the efficacy of trtE against Cryptosporidium infection in the setting of severe immunosuppression and in a ruminant model of cryptosporidiosis. A. We will test trtE’s ability to inhibit and eliminate Cryptosporidium infection in NOD-SCID gamma mice. B. Because mice do not manifest the symptoms of human disease, we will test the trtE’s ability to inhibit infection and diarrheal illness in neonatal lambs. Aim 4: To optimize production of trtE from Teredinibacter turnerae T7901: Like many natural products, trtE has a complex structure that renders synthesis challenging and prohibitively expensive. The Natural Products Discovery Institute (NPDI), experts in the field of natural product production, will be producing trtE for these studies using established protocols. During that process, NPDI will apply their expertise in this area to increase production efficiency. These studies will provide data essential to establish trtE as a lead candidate for an anti-Cryptosporidium therapeutic. Moreover, because this compound is highly active against multiple parasites, these investigations will underpin future studies evaluating this compound as a broad spectrum therapeutic for diseases caused by apicomplexan parasites, but most critically for cryptosporidiosis, a neglected disease of world-wide significance for which there are no good therapeutic options.


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 = $164,781 )
2024	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	3	2/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$164,781
														Subtotal = $164,781

Issue Date FY: 2023 ( Subtotal = $186,542 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	5	5/23/2023	NON-COMPETING CONTINUATION	$351,323
2023	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	1	2/27/2023	NEW	-$164,781
														Subtotal = $186,542

Issue Date FY: 2022 ( Subtotal = $425,214 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	002	4	5/31/2022	NON-COMPETING CONTINUATION	$424,141
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	3	1/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$429,156
2022	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	2	1/31/2022	NON-COMPETING CONTINUATION	-$428,083
														Subtotal = $425,214

Issue Date FY: 2021 ( Subtotal = $428,083 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	2	5/6/2021	NON-COMPETING CONTINUATION	$428,083
														Subtotal = $428,083

Issue Date FY: 2020 ( Subtotal = $474,114 )
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	1	6/11/2020	NEW	$474,114
														Subtotal = $474,114

Grand Total All Awards = $1,678,734

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Development of a new marine natural product for the treatment of cryptosporidiosis, an AIDS-defining disease

Award Number: R01AI154943

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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