HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Stevens, Mckayla¹  Abdeen, Sanofar¹  Salim, Nilshad¹  Ray, Anne-Marie¹  Washburn, Alex¹  Chitre, Siddhi¹  Sivinski, Jared²  Park, Yangshin^1,3,4  Hoang, Quyen Q.^1,3,4  Chapman, Eli²  Johnson, Steven M.¹ 

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

[2] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, 1703 E Mabel St,POB 210207, Tucson, AZ 85721 USA

[3] Indiana Univ, Stark Neurosci Res Inst, Sch Med, 320 W 15th St,Suite 414, Indianapolis, IN 46202 USA

[4] Indiana Univ, Dept Neurol, Sch Med, 635 Barnhill Dr, Indianapolis, IN 46202 USA

关键词: GroEL;    GroES;    HSP60;    HSP10;    Molecular chaperone;    Chaperonin;    Proteostasis;    Small molecule inhibitors;    Natural products;   

DOI  :  10.1016/j.bmcl.2019.02.028

来源: Elsevier

【 摘 要 】

All living organisms contain a unique class of molecular chaperones called 60 kDa heat shock proteins (HSP60 also known as GroEL in bacteria). While some organisms contain more than one HSP60 or GroEL isoform, at least one isoform has always proven to be essential. Because of this, we have been investigating targeting HSP60 and GroEL chaperonin systems as an antibiotic strategy. Our initial studies focused on applying this antibiotic strategy for treating African sleeping sickness (caused by Trypanosoma brucei parasites) and drug-resistant bacterial infections (in particular Methicillin-resistant Staphylococcus aureus - MRSA). Intriguingly, during our studies we found that three known antibiotics - suramin, closantel, and rafoxanide - were potent inhibitors of bacterial GroEL and human HSP60 chaperonin systems. These findings prompted us to explore what other approved drugs, natural products, and known bioactive molecules might also inhibit HSP60 and GroEL chaperonin systems. Initial high-throughput screening of 3680 approved drugs, natural products, and known bioactives identified 161 hit inhibitors of the Escherichia coli GroEL chaperonin system (4.3% hit rate). From a purchased subset of 60 hits, 29 compounds (48%) re-confirmed as selective GroEL inhibitors in our assays, all of which were nearly equipotent against human HSP60. These findings illuminate the notion that targeting chaperonin systems might be a more common occurrence than we previously appreciated. Future studies are needed to determine if the in vivo modes of action of these approved drugs, natural products, and known bioactive molecules are related to GroEL and HSP60 inhibition.

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