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 • US Army Medical Research and Development Command
Publication Number
US-11414385-B2
Publication Date
2022-08-16
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 problem being solved arises from apicomplexan parasitic infections such as Toxoplasma gondii, which cause systemic symptoms, damage tissues (especially the eye and brain), and fatalities. Current treatments are limited to active tachyzoites and carry side effects that limit their use. Notably, latent bradyzoites in dormant cysts are not effectively treated by existing medicines, making infections incurable with lifelong recrudescence. Resistance to partial treatments like atovaquone develops with clinical use. There is an urgent need for improved medicines due to the high disease burden and substantial treatment costs.
Existing methods have critical flaws such as lack of in vitro culture systems for cysts and scalable animal models for drug screening. The invention addresses this by characterizing the EGS T. gondii strain, which forms true cysts in vitro that produce oocysts in cats, providing a validated in vitro model for the dormant bradyzoite phenotype. The cell lines infected with these parasites affect host cell pathways related to ribosomal function, protein misfolding, oxidative pathways and neurodegenerative diseases. These models enable screening of candidate compounds that inhibit cyst formation or parasite replication, facilitating development of medicines against active and latent apicomplexan infections.
Claims Coverage
The patent contains one independent claim focused on compounds of Formula (I) and their pharmaceutical compositions and methods of use.
Compound of Formula (I) and pharmaceutically acceptable salts
The invention claims compounds defined by Formula (I), which include variations such as stereoisomers and pharmaceutically acceptable salts, with specific chemical structures where ring A forms C3-7 cycloalkenyl or heteroaryl ring with various substitutions.
The independent claim encompasses novel chemical compounds characterized by the specified structural parameters, their pharmaceutical compositions, and therapeutic methods of treating apicomplexan parasite infections using these compounds or compositions.
Stated Advantages
The compounds demonstrate potent inhibition of Toxoplasma gondii tachyzoites and bradyzoites, as well as Plasmodium falciparum, including drug-resistant strains, with effects observed in vitro and in vivo.
Improved solubility and pharmacokinetic properties, such as ability to cross the blood-brain barrier and reduced toxicity compared to prior quinolone inhibitors, enable better drug delivery and therapeutic potential.
The use of novel cell line and animal models possessing the true dormant parasite phenotype enables identification and validation of effective compounds against latent apicomplexan infections.
Methods employing transcriptomic signatures allow targeting parasite and host pathways critical for infection and persistence, providing additional therapeutic strategies and biomarkers.
Documented Applications
Treatment of apicomplexan parasitic infections, including Toxoplasma gondii infections and Plasmodium falciparum infections in humans and non-human animals.
Use of cell lines infected with specific apicomplexan parasites exhibiting dormant bradyzoite cysts for screening and identifying candidate therapeutic compounds.
Use of non-human animal models comprising the infected cell lines or oocysts derived therefrom for evaluation of drug efficacy and disease progression.
Monitoring apicomplexan infection and response to therapy by detecting expression or levels of specific host or parasite biomarkers in biological samples.
Combination therapy comprising the compounds of Formula (I) with 8-aminoquinoline drugs such as tafenoquine to target various lifecycle stages.
Use of biomarkers such as clusterin, oxytocin, PGLYRP2, ApoA1, and certain miRNAs for diagnosis or monitoring of T. gondii infection and associated neurodegeneration.
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