Identification and Optimization of Inhibitors of Trypanosomal Cysteine Proteases: Cruzain, Rhodesain, and TbCatB

被引：103

作者：

Mott, Bryan T. ^{[1
]}

Ferreira, Rafaela S. ^{[2
,4
,5
]}

Simeonov, Anton ^{[1
]}

Jadhav, Ajit ^{[1
]}

Ang, Kenny Kean-Hooi ^{[3
]}

Leister, William ^{[1
]}

Shen, Min ^{[1
]}

Silveira, Julia T. ^{[1
]}

Doyle, Patricia S. ^{[5
]}

Arkin, Michelle R. ^{[3
]}

McKerrow, James H. ^{[5
]}

Inglese, James ^{[1
]}

Austin, Christopher P. ^{[1
]}

Thomas, Craig J. ^{[1
]}

Shoichet, Brian K. ^{[2
]}

Maloney, David J. ^{[1
]}

机构：

[1] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA

[2] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Grad Program Chem & Chem Biol, San Francisco, CA 94158 USA

[5] Univ Calif San Francisco, Sandler Ctr Basic Res Parasit Dis, San Francisco, CA 94158 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 01期

基金：

美国国家卫生研究院;

关键词：

CHAGAS-DISEASE; CATHEPSIN-B; MOUSE MODEL; INFECTION; POTENT; MECHANISM; LIBRARIES; BRUCEI;

D O I：

10.1021/jm901069a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：52 / 60

页数：9

共 33 条

[1] RNA Interference of Trypanosoma brucei Cathepsin B and L Affects Disease Progression in a Mouse Model [J].