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Antiparasitic metabolites from deep subterranean fungi for the treatment of cryptosporidiosis, an AIDS defining disease

Award Number: R21AI177019
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Cryptosporidium, an AIDS-defining pathogen and one of the most common causes of diarrheal disease worldwide, still lacks any effective therapeutic options. Despite recent advances, there are too few drugs in the development pipeline to guarantee success in advanced clinical trials. A screen of compounds produced by fungi isolated from deep within the Soudan Iron Mine in northern Minnesota identified a set of 14 related norditerpene lactones from Oidiodendron truncatum, eight of which have activity against Cryptosporidium and three against Toxoplasma, with no cytotoxicity to mammalian host cells. The discovery of a natural, synthesizable derivative series that includes compounds with nanomolar activity against two opportunistic pathogens allows for a detailed structure activity relationship (SAR) study that can be quickly built upon to generate an optimal compound for entry into preclinical studies. We hypothesize that this newly discovered anti-parasitic scaffold will yield a compound with in vivo activity and pharmacokinetic parameters favorable for therapeutic development. We further hypothesize that these compounds will identify a new druggable target in apicomplexans. We propose to test these hypotheses in two specific aims: Aim 1: Determine anti-parasitic efficacy and pharmacokinetic properties of the derivative series. In this aim we will determine EC50s, selectivity indices and ADME/PK parameters of active compounds and use these data to choose compounds for testing in Cryptosporidium-infected severely immunocompromised mice. An exploratory sub-aim will identify and test additional minor structural analogs to expand the structure activity relationship studies. Aim 2: Identify the molecular target of the most potent Oidiodendron derivatives. In this aim we propose to take advantage of the anti-Toxoplasma activity of three of the derivatives to conduct a forward genetics experiment to identify the target of the compounds. In parallel, drug affinity responsive target stability assays will be conducted with Toxoplasma and Cryptosporidium lysates to complement the data obtained from the genetics approach. Potential homologs in other apicomplexans will be identified by bioinformatics. Natural products have a proven track record as effective and robust therapeutics for parasitic diseases; one need look no farther than artemisinin and ivermectin to grasp the potential of the Oidiodendron derivatives for development of a new anti-Cryptosporidium therapeutic. The dual activity of some of the derivatives opens up the possibility that the compound(s) may also be effective against AIDS-associated toxoplasmosis. These studies are ideal for the R21 mechanism as they are exploratory and high-risk/high return, potentially providing a new therapeutic pharmacophore and a new therapeutic target for untreatable cryptosporidiosis.


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 = $209,250 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	2	2/14/2024	NON-COMPETING CONTINUATION	$209,250
														Subtotal = $209,250

Issue Date FY: 2023 ( Subtotal = $193,750 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	2/28/2023	NEW	$193,750
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	1	6/2/2023	NEW	$0
														Subtotal = $193,750

Grand Total All Awards = $403,000

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Antiparasitic metabolites from deep subterranean fungi for the treatment of cryptosporidiosis, an AIDS defining disease

Award Number: R21AI177019

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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