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

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2024 · $232,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10797019
- **Project number:** 5R21AI177019-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** ROBERTA M O'CONNOR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $232,500
- **Award type:** 5
- **Project period:** 2023-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797019

## Citation

> US National Institutes of Health, RePORTER application 10797019, Antiparasitic metabolites from deep subterranean fungi for the treatment of cryptosporidiosis, an AIDS defining disease (5R21AI177019-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10797019. Licensed CC0.

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