Compounds and methods for treating, detecting, and identifying compounds to treat apicomplexan parasitic diseases
Inventors
McLeod, Rima • McPhillie, Martin • Fishwick, Colin W. G. • Lorenzi, Hernan Alejandro • Wang, Kai • Kim, Taek-Kyun • Zhou, Yong • Hood, Leroy E. • Zhou, Ying • El Bissati, Kamal • Hickman, Mark • Li, QiGui • Roberts, Craig
Assignees
University of Sheffield • University of Leeds • University of Strathclyde • University of Chicago • Institute for Systems Biology • J Craig Venter Institute Inc • United States Department of the Army • Government of the United States of America
Publication Number
US-11964944-B2
Publication Date
2024-04-23
Expiration Date
2036-12-20
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Abstract
Disclosed herein are novel compounds for treating apicomplexan parasite related disorders, methods for their use; cell line and non-human animal models of the dormant parasite phenotype and methods for their use in identifying new drugs to treat apicomplexan parasite related disorders, and biomarkers to identify disease due to the parasite and its response to treatment.
Core Innovation
The invention provides novel compounds of specific chemical structures, specifically 4-(1H)-quinolone scaffolds such as substituted 5,6,7,8-tetrahydroquinolin-4-ones, pharmaceutical compositions thereof, and methods for their use in treating apicomplexan parasite-related disorders, including Toxoplasma gondii infections. These compounds act as potent inhibitors of the cytochrome bc1 complex Qi site of apicomplexan parasites, showing efficacy against both active tachyzoite and dormant bradyzoite forms, as well as drug-resistant Plasmodium falciparum strains, with improved solubility and pharmacologic properties compatible with crossing the blood-brain barrier.
The invention addresses critical limitations in current treatments and models for apicomplexan parasitic infections. Specifically, apicomplexan parasites such as Toxoplasma gondii cause systemic disease with damage to eye and brain tissues and remain incurable due to resistant latent cysts. Existing treatments target tachyzoites but have side effects and fail to affect latent bradyzoites. There is an urgent need for improved medicines, especially compounds effective against dormant cyst forms. Challenges include lack of in vitro culture systems for cysts and scalable animal models for drug screening. The invention provides characterized cell lines infected with an apicomplexan parasite with a mutated Apetela 2 IV-4 protein (M570I) that possess a true dormant bradyzoite phenotype and methods utilizing these cell lines and non-human animal models for drug identification.
The invention further provides compositions comprising isolated probes selective for markers upregulated in cells infected with an apicomplexan parasite, enabling diagnostics and monitoring of infection and treatment efficacy. Methods for monitoring T. gondii infection in subjects by measuring specific biomarkers such as clusterin, oxytocin, PGLYRP2, Apolipoprotein A1, and microRNAs are also disclosed, as well as methods for treating infection by administering ApoA1. Altogether, the invention integrates novel chemical compounds, biological models, diagnostic probes, and treatment approaches to advance understanding and therapy of apicomplexan parasitic diseases.
Claims Coverage
The patent includes 15 claims covering chemical compounds, pharmaceutical compositions, treatment methods, diagnostic methods, cell lines, and probes related to apicomplexan parasitic diseases. The independent claims focus on the novel compounds of Formula (I), their pharmaceutical use, diagnostic markers, and cell lines harboring mutated Apetela 2 IV-4 proteins.
Compounds of specific chemical structures
Provided are compounds of Formula (I) and related stereoisomers and pharmaceutically acceptable salts, characterized by a detailed chemical structure with substituents, where ring A forms cycloalkenyl or heteroaryl rings, and various chemical groups are defined for Y1, Y2, X1, X2, X3, X4, X5, R1, R2, R3, and R.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions containing a compound of Formula (I) and pharmaceutically acceptable diluents, excipients, or carriers are provided, including compositions combining compounds of Formula (I) with 8-Aminoquinoline drugs such as tafenoquine.
Methods of treating apicomplexan parasitic infections
Methods comprising administering to a subject in need an effective amount of a compound or pharmaceutical composition of Formula (I) to treat apicomplexan parasite infections, such as Toxoplasma gondii or Plasmodium falciparum infections, including infections in the brain or eye and in immune-compromised subjects.
Methods for monitoring treatment efficacy
Methods for monitoring treatment of an apicomplexan parasitic infection by detecting changes in expression, protein levels, or activity of one or more specific markers, where changes indicate treatment effectiveness.
Cell line infected with apicomplexan parasite encoding mutated Apetela 2 IV-4
Provision of a cell line infected with an apicomplexan parasite whose genome encodes an Apetela 2 IV-4 protein with an M570I mutation compared to the orthologous gene in T. gondii ME49 strain.
Methods for identifying candidate therapeutic compounds
Methods for identifying test compounds that modulate (reduce or increase) expression of specified apicomplexan parasite genes to discover potential therapeutic agents.
Compositions of isolated probes for markers of infection
Compositions of isolated probes selectively binding to markers upregulated in human fibroblasts, neuronal stem cells, or monocytic lineage cells after infection with T. gondii, useful for diagnosis or monitoring.
The patent covers novel and specially structured chemical compounds effective against apicomplexan parasites, compositions containing them, methods treating infections using these compounds, diagnostic and monitoring methods based on specific biomarkers, unique infected cell lines with mutated transcription factor genes, and methods for discovering new therapeutics by gene expression modulation. These features collectively offer a comprehensive approach to apicomplexan parasitic disease treatment and diagnosis.
Stated Advantages
The compounds have improved aqueous solubility and pharmacologic properties that enable them to cross the blood-brain barrier.
The novel compounds inhibit both active tachyzoite and latent bradyzoite forms of apicomplexan parasites, addressing recrudescence issues.
The use of cell lines with a true bradyzoite dormant phenotype and in vivo models that produce oocysts allows for improved and scalable drug screening.
Identified biomarkers provide means for monitoring infection status and treatment efficacy in human subjects.
Documented Applications
Treatment of apicomplexan parasite related disorders, including infections by Toxoplasma gondii and Plasmodium falciparum in various forms such as brain and eye infections.
Use of infected cell lines and non-human animal models for identifying compounds effective against apicomplexan parasitic infections.
Diagnostic and monitoring methods for T. gondii infection by measuring specific circulating biomarkers in biological samples from subjects.
Administration of ApoA1 as a therapy for T. gondii infection in subjects with reduced serum levels.
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