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Bioorg Med Chem Lett. 2016 Nov 1;26(21):5247-5253. doi: 10.1016/j.bmcl.2016.09.051. Epub 2016 Sep 22.

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

Author information

1
Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
2
Yale School of Public Health, Department of Epidemiology of Microbial Diseases, 60 College St., New Haven, CT 06520, United States.
3
The Scripps Research Institute, Department of Chemistry, 10550 North Torrey Pines Rd., La Jolla, CA 92037, United States.
4
HHMI, Department of Genetics, Yale School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave., New Haven, CT 06510, United States.
5
The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., Tucson, AZ 85721, United States.
6
Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States. Electronic address: johnstm@iu.edu.

Abstract

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 3.1μM, 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.

KEYWORDS:

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

PMID:
27720295
DOI:
10.1016/j.bmcl.2016.09.051
[Indexed for MEDLINE]

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