# Optimizing CDPK1 inhibitors for chronic toxoplasmosis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $787,253

## Abstract

PROJECT SUMMARY
Toxoplasma gondii is an opportunistic pathogen that causes disease in immunocompromised patients and in
infants due to congenital infections. Following a brief acute phase, the parasite differentiates into a semi-
dormant form called the bradyzoite, which resides within long-lived tissue cysts that are primarily located in the
central nervous system (CNS). Despite a vigorous immune response, tissue cysts are not eliminated and they
pose a risk of reactivation when immunity wanes. It is estimated that ~2 billion people worldwide are
chronically infected with T. gondii and hence at risk of reactivation should their immune function decline. In
many regions of South America, infection can lead to severe and recurrent ocular disease in
immunocompetent individuals. Chemotherapy is available for acute toxoplasmosis based on a combination of
pyrimethamine and sulfadiazine. However, there are complications due to the toxicity of pyrimethamine and
allergic reactions to sulfa drugs. Moreover, this treatment poses risks during pregnancy due to teratogenicity.
Current treatment is effective in controlling acute infection, but has minimal effect on chronic tissue cyst stages
and hence is not curative. Although a number of new compounds have been shown to inhibit T. gondii growth
in vitro, most have little effect on the chronic stage. Hence, there is a major need for new efforts to identify
compounds for treating chronic toxoplasmosis.
 The goal of this project is to identify late stage preclinical leads that show potent inhibition of parasite
growth in vitro, eliminate chronic infection in vivo, and that possess appropriate ADME and safety profiles for
advancement. We will develop potent and selective inhibitors of TgCDPK1, which is an unique and essential
enzyme in T. gondii. In preliminary studies, we have identified several lead compounds that are both highly
potent and selective for TgCDPK1 over mammalian kinases. We will design and synthesize new analogs to
improve potency, selectivity, CNS penetration, bioavailability, and ADMET-PK properties of these compounds.
Specific criteria for potency, selectivity and ADMET properties will be used to advance compounds to in vivo
testing. We have developed new quantitative assays for monitoring inhibition of acute and chronic stages of
infection and we will employ animal models for monitoring the efficacy of compounds against reactivated
toxoplasmosis in the CNS. Successful achievement of these milestones will deliver lead compound(s) for
future IND-enabling studies with the eventual goal of curing chronic toxoplasmosis.

## Key facts

- **NIH application ID:** 10457052
- **Project number:** 1R01AI164473-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** James W Janetka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $787,253
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457052

## Citation

> US National Institutes of Health, RePORTER application 10457052, Optimizing CDPK1 inhibitors for chronic toxoplasmosis (1R01AI164473-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10457052. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*