期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 1, 页码 52-60出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm901069a
关键词
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资金
- National Institutes of Health Roadmap for Medical Research
- NIH [GM59957]
- Sandler Center for Basic Research in Parasitic Diseases
Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas' disease and African sleeping sickness, respectively. Both parasites rely oil 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, its 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 it panel of human cysteine and serine proteases to determine selectivity, and it cocrystal was obtained of our most potent analogue bound to cruzain.
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