Identification and optimization of inhibitors of Trypanosomal cysteine proteases: cruzain, rhodesain, and TbCatB.
نویسندگان
چکیده
Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely on essential cysteine proteases for survival: cruzain for T. cruzi and TbCatB/rhodesain for T. brucei. A recent quantitative high-throughput screen of cruzain identified triazine nitriles, which are known inhibitors of other cysteine proteases, as reversible inhibitors of the enzyme. Structural modifications detailed herein, including core scaffold modification from triazine to purine, improved the in vitro potency against both cruzain and rhodesain by 350-fold, while also gaining activity against T. brucei parasites. Selected compounds were screened against a panel of human cysteine and serine proteases to determine selectivity, and a cocrystal was obtained of our most potent analogue bound to cruzain.
منابع مشابه
Crystal Structures of TbCatB and Rhodesain, Potential Chemotherapeutic Targets and Major Cysteine Proteases of Trypanosoma brucei
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ورودعنوان ژورنال:
- Journal of medicinal chemistry
دوره 53 1 شماره
صفحات -
تاریخ انتشار 2010