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Discovery and Optimization of Triazine Nitrile Inhibitors of Toxoplasma gondii Cathepsin L for the Potential Treatment of Chronic Toxoplasmosis in the CNS
journal contribution
posted on 2020-02-18, 17:36 authored by Jeffery
D. Zwicker, David Smith, Alfredo J. Guerra, Jacob R. Hitchens, Nicole Haug, Steve Vander Roest, Pil Lee, Bo Wen, Duxin Sun, Lu Wang, Richard F. Keep, Jianming Xiang, Vern B. Carruthers, Scott D. LarsenWith roughly 2 billion people infected,
the neurotropic protozoan Toxoplasma gondii remains
one of the most pervasive and
infectious parasites. Toxoplasma infection is the
second leading cause of death due to foodborne illness in the United
States, causes severe disease in immunocompromised patients, and is
correlated with several cognitive and neurological disorders. Currently,
no therapies exist that are capable of eliminating the persistent
infection in the central nervous system (CNS). In this study we report
the identification of triazine nitrile inhibitors of Toxoplasma cathepsin L (TgCPL) from a high throughput screen
and their subsequent optimization. Through rational design, we improved
inhibitor potency to as low as 5 nM, identified pharmacophore features
that can be exploited for isoform selectivity (up to 7-fold for TgCPL versus human isoform), and improved metabolic stability
(t1/2 > 60 min in mouse liver microsomes)
guided by a metabolite ID study. We demonstrated that this class of
compounds is capable of crossing the blood-brain barrier in mice (1:1
brain/plasma at 2 h). Importantly, we also show for the first time
that treatment of T. gondii bradyzoite cysts in vitro
with triazine nitrile inhibitors reduces parasite viability with efficacy
equivalent to a TgCPL genetic knockout.