Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Apr 20:5:35.
doi: 10.3389/fmolb.2018.00035. eCollection 2018.

Toward Developing Chemical Modulators of Hsp60 as Potential Therapeutics

Qianli Meng  1 , Bingbing X Li  1 , Xiangshu Xiao  1
Affiliations
Review

Toward Developing Chemical Modulators of Hsp60 as Potential Therapeutics

Qianli Meng et al. Front Mol Biosci. .

Abstract

The 60 kDa heat shock protein (Hsp60) is classically known as a mitochondrial chaperonin protein working together with co-chaperonin 10 kDa heat shock protein (Hsp10). This chaperonin complex is essential for folding proteins newly imported into mitochondria. However, Hsp60, and/or Hsp10 have also been shown to reside in other subcellular compartments including extracellular space, cytosol, and nucleus. The proteins in these extra-mitochondrial compartments may possess a wide range of functions dependent or independent of its chaperoning activity. But the mechanistic details remain unknown. Mutations in Hsp60 gene have been shown to be associated with neurodegenerative disorders. Abnormality in expression level and/or subcellular localization have also been detected from different diseased tissues including inflammatory diseases and various cancers. Therefore, there is a strong interest in developing small molecule modulators of Hsp60. Most of the reported inhibitors were discovered through various chemoproteomics strategies. In this review, we will describe the recent progress in this area with reported inhibitors from both natural products and synthetic compounds. The former includes mizoribine, epolactaene, myrtucommulone, stephacidin B, and avrainvillamide while the latter includes o-carboranylphenoxyacetanilides and gold (III) porphyrins. The potencies of the known inhibitors range from low micromolar to millimolar concentrations. The potential applications of these inhibitors include anti-cancer, anti-inflammatory diseases, and anti-autoimmune diseases.

Keywords: GroEL; GroES; Hsp10; Hsp60; autoimmune; cancer; chaperone; inhibitor.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical structure of mizoribine (1).
Figure 2
Figure 2
Chemical structures of epolactaene (2) and its tert-butyl ester ETB (3).
Figure 3
Figure 3
Binding site of ETB on Hsp60. (A) The Hsp60-Hsp10 complex (PDB: 4PJ1) is color-coded in red (Hsp10) and green (Hsp60) cartoons. The ADP molecules are presented in stick model in red and Cys442 residues are presented in stick model in yellow. (B) Close-up of the ADP binding pocket along with Cys442 in Hsp60.
Figure 4
Figure 4
Chemical structure of myrtucommulone A (MC, 4).
Figure 5
Figure 5
Chemical structures Stephacidin B (5), avrainvillamide (6), and a simplified analog 7.
Figure 6
Figure 6
Chemical structures of o-carboranylphenoxyacetanilide 8 and its clickable photoaffinity probe 9.
Figure 7
Figure 7
Chemical structure of gold (III) porphyrin [Au(TPP)]Cl (10) and its clickable photoaffinity probe 11.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Abdeen S., Salim N., Mammadova N., Summers C. M., Frankson R., Ambrose A. J., et al. . (2016a). GroEL/ES inhibitors as potential antibiotics. Bioorg. Med. Chem. Lett. 26, 3127–3134. 10.1016/j.bmcl.2016.04.089 - DOI - PubMed
    1. Abdeen S., Salim N., Mammadova N., Summers C. M., Goldsmith-Pestana K., McMahon-Pratt D., et al. . (2016b). Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness. Bioorg. Med. Chem. Lett. 26, 5247–5253. 10.1016/j.bmcl.2016.09.051 - DOI - PubMed
    1. Anfinsen C. B. (1973). Principles that govern the folding of protein chains. Science 181, 223–230. 10.1126/science.181.4096.223 - DOI - PubMed
    1. Appendino G., Bianchi F., Minassi A., Sterner O., Ballero M., Gibbons S. (2002). Oligomeric acylphloroglucinols from myrtle (Myrtus communis). J. Nat. Prod. 65, 334–338. 10.1021/np010441b - DOI - PubMed
    1. Astarloa R., Castrillo J. C. M. (1996). Humoral response to the human heat shock 60 kDa protein in myasthenia gravis. J. Neurol. Sci. 135, 182–183. 10.1016/0022-510X(95)00191-4 - DOI - PubMed
-