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

Stevens, Mckayla; Abdeen, Sanofar; Salim, Nilshad; Ray, Anne‐Marie; Washburn, Alex; Chitre, Siddhi; Sivinski, Jared; Park, Yangshin; Hoang, Quyen Q.; Chapman, Eli; Johnson, Steven M.

doi:10.1016/j.bmcl.2019.02.028

Cited by 26 publications

(19 citation statements)

References 49 publications

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“…For these reasons, interest in Hsp60 has been steadily increasing in recent years, especially because it holds promise for developing new diagnostic and therapeutic procedures pertinent to common and serious chaperonopathies such as various types of cancer, and inflammatory and autoimmune disorders as well as for a range of neurodegenerative diseases (Macario and Conway de Macario, 2005;Cappello et al, 2008;Bross et al, 2012;Cappello et al, 2013Cappello et al, , 2014Marino Gammazza et al, 2016Campanella et al, 2018;Meng et al, 2018;Hoter et al, 2019;van Eden et al, 2019). For example, Hsp60 inhibitors and modulators are being actively evaluated as novel anti-cancer agents (Wang et al, 2013;Cappello et al, 2014;Meng et al, 2018;Stevens et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Bavisotto

Alberti

Vitale

et al. 2020

Front. Mol. Biosci.

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Hsp60 is a chaperone belonging to the Chaperonins of Group I and typically functions inside mitochondria in which, together with the co-chaperonin Hsp10, maintains protein homeostasis. In addition to this canonical role, Hsp60 plays many others beyond the mitochondria, for instance in the cytosol, plasma-cell membrane, extracellular space, and body fluids. These non-canonical functions include participation in inflammation, autoimmunity, carcinogenesis, cell replication, and other cellular events in health and disease. Thus, Hsp60 is a multifaceted molecule with a wide range of cellular and tissue locations and functions, which is noteworthy because there is only one hsp60 gene. The question is by what mechanism this protein can become multifaceted. Likely, one factor contributing to this diversity is post-translational modification (PTM). The amino acid sequence of Hsp60 contains many potential phosphorylation sites, and other PTMs are possible such as O-GlcNAcylation, nitration, acetylation, S-nitrosylation, citrullination, oxidation, and ubiquitination. The effect of some of these PTMs on Hsp60 functions have been examined, for instance phosphorylation has been implicated in sperm capacitation, docking of H2B and microtubule-associated proteins, mitochondrial dysfunction, tumor invasiveness, and delay or facilitation of apoptosis. Nitration was found to affect the stability of the mitochondrial permeability transition pore, to inhibit folding ability, and to perturb insulin secretion. Hyperacetylation was associated with mitochondrial failure; S-nitrosylation has an impact on mitochondrial stability and endothelial integrity; citrullination can be pro-apoptotic; oxidation has a role in the response to cellular injury and in cell migration; and ubiquitination regulates interaction with the ubiquitin-proteasome system. Future research ought to determine which PTM causes which variations in the Hsp60 molecular properties and functions, and which of them are pathogenic, causing chaperonopathies. This is an important topic considering the number of acquired Hsp60 chaperonopathies already cataloged, many of which are serious diseases without efficacious treatment.

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Section: Introductionmentioning

confidence: 99%

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Bavisotto

Alberti

Vitale

et al. 2020

Front. Mol. Biosci.

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“…The screening of 77 compounds resulted in the identification of 22 chemical and pharmacological chaperones (hit rate: 29 %). Compared to other screening campaigns, this hit rate is extremely high (Nühs et al, 2015;Atzmon et al, 2018;Stevens et al, 2019) but can be explained by: (i) We specifically selected known ion channel antagonists for the screening. (ii) A large number of active compounds were structurally related.…”

Section: Discussionmentioning

confidence: 99%

Identification of Chemical and Pharmacological Chaperones for Correction of Trafficking-Deficient Mutant Cyclic Nucleotide–Gated A3 Channels

Täger¹,

Wissinger

Kohl

et al. 2021

Mol Pharmacol

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Trafficking deficiency caused by missense mutations is a well-known phenomenon occurring for mutant, misfolded proteins. Typically, the misfolded protein is retained by the protein quality control system and degraded by the endoplasmic reticulum-associated protein degradation pathway and thus does not reach its destination although residual function of the protein may be preserved. Chemical and pharmacological chaperones can improve the targeting of trafficking-deficient proteins and thus may be promising candidates for therapeutic applications. Here, we report the application of a cellular bioassay based on the bioluminescent calcium reporter aequorin to quantify surface expression of mutant CNGA3 channels associated with the autosomal-recessively inherited retinal disease achromatopsia. A screening of 77 compounds enabled the identification of effective chemical and pharmacological chaperones resulting in a 1.5 to 4.8 fold increase of surface expression of mutant CNGA3. We confirmed that the rescue of the defective trafficking is not limited to a single mutation in CNGA3 using selected compounds. Active compounds and our structure-activity correlated data for the dihydropyridine compound class may provide valuable information for developing a treatment of the trafficking defect in achromatopsia.

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“…Most of the compounds known to inhibit parasite Hsp60/10 chaperone systems have low selectivity, as they inhibit Escherichia coli GroEL/ES and human Hsp60/10 in vitro [124]. Suramin, a polysulphonated symmetrical naphthalene derivative and a potent inhibitor of the Hsp60/10 chaperone system, is used as first line chemotherapeutic agent against T. brucei gambiense and T. brucei rhodesiense ), an agent for African sleeping sickness (Figure 6) [125].…”

Section: Hsp60 Familymentioning

confidence: 99%

“…Another promising anticancer drug, KHS101, selectively targets glioblastoma cells, which makes it a useful lead towards further development of inhibitors of Hsp60s of parasitic origin [134]. Known Hsp60 inhibitors abrogate the refolding activity of the chaperonin without affecting its ATPase activity [124]. However, their broad mechanism of action is still to be defined.…”

Section: Hsp60 Familymentioning

confidence: 99%

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

Zininga

Shonhai

2019

IJMS

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Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.

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

Cited by 26 publications

References 49 publications

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Hsp60 Post-translational Modifications: Functional and Pathological Consequences

Identification of Chemical and Pharmacological Chaperones for Correction of Trafficking-Deficient Mutant Cyclic Nucleotide–Gated A3 Channels

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

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