title: Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness.
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.
authors.affiliation: Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
authors.forename: Sanofar
authors.initials: S
authors.lastname: Abdeen
authors.affiliation: Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
authors.forename: Nilshad
authors.initials: N
authors.lastname: Salim
authors.affiliation: Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
authors.forename: Najiba
authors.initials: N
authors.lastname: Mammadova
authors.affiliation: Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States.
authors.forename: Corey M
authors.initials: CM
authors.lastname: Summers
authors.affiliation: Yale School of Public Health, Department of Epidemiology of Microbial Diseases, 60 College St., New Haven, CT 06520, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.affiliation: Yale School of Public Health, Department of Epidemiology of Microbial Diseases, 60 College St., New Haven, CT 06520, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
authors.affiliation: The Scripps Research Institute, Department of Chemistry, 10550 North Torrey Pines Rd., La Jolla, CA 92037, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: HHMI, Department of Genetics, Yale School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Ave., New Haven, CT 06510, United States.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Horwich
authors.affiliation: The University of Arizona, College of Pharmacy, Department of Pharmacology and Toxicology, 1703 E. Mabel St., Tucson, AZ 85721, United States.
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.affiliation: Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, United States. Electronic address: johnstm@iu.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018835:Chaperonin 10 / Q000187:drug effects*; D018834:Chaperonin 60 / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D000981:Antiprotozoal Agents; D018835:Chaperonin 10; D018834:Chaperonin 60
keywords: African sleeping sickness; Antibiotics; Chaperonin; GroEL; GroES; HSP10; HSP60; Molecular chaperone; Parasites; Proteostasis; Small molecule inhibitors; Trypanosoma brucei