Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Abdeen, Sanofar¹  Salim, Nilshad¹  Mammadova, Najiba^1,6  Summers, Corey M.^1,7  Goldsmith-Pestana, Karen²  McMahon-Pratt, Diane²  Schultz, Peter G.³  Horwich, Arthur L.⁴  Chapman, Eli⁵  Johnson, Steven M.¹ 

[1] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, 635 Barnhill Dr, Indianapolis, IN 46202 USA

[2] Yale Sch Publ Hlth, Dept Epidemiol Microbial Dis, 60 Coll St, New Haven, CT 06520 USA

[3] Scripps Res Inst, Dept Chem, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA

[4] Yale Sch Med, Dept Genet, HHMI, Boyer Ctr Mol Med, 295 Congress Ave, New Haven, CT 06510 USA

[5] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, 1703 E Mabel St, Tucson, AZ 85721 USA

[6] Iowa State Univ, Dept Genet Dev & Cell Biol, 1210 Mol Biol Bldg,Pannel Dr, Ames, IA 50011 USA

[7] Iowa State Univ, Dept Kinesiol, 235 Barbara E Forker Bldg,Beach Rd, Ames, IA 50011 USA

关键词: GroEL;    GroES;    HSP60;    HSP10;    Molecular chaperone;    Chaperonin;    Proteostasis;    Small molecule inhibitors;    Antibiotics;    Parasites;    Trypanosoma brucei;    African sleeping sickness;   

DOI  :  10.1016/j.bmcl.2016.09.051

来源: Elsevier

【 摘 要 】

Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC50 = 7.9 and 3.1 mu M, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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