Mimicking Molecular Chaperones to Regulate Protein Folding

Ma, Feihe; Li, Chang; Liu, Yang; Shi, Linqi

doi:10.1002/adma.201805945

“… Chaperone‐mimicking NPs or “artificial chaperones” which mimic the structure and behavior of chaperones [10, 33] Chaperone‐aiding NPs or “chemical chaperones”, which have chaperone‐like functions by assisting (re)folding, stabilizing unfolded proteins, mediating degradation, and assisting protein assembly [10] …”

Section: Nanochaperones To Treat Misfolding Diseasesmentioning

confidence: 99%

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

Caballero

¹

,

Gámez

²

2020

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The generation of highly organized amyloid fibrils is associated with a wide range of conformational pathologies, including primarily neurodegenerative diseases. Such disorders are characterized by misfolded proteins that lose their normal physiological roles and acquire toxicity. Recent findings suggest that proteostasis network impairment may be one of the causes leading to the accumulation and spread of amyloids. These observations are certainly contributing to a new focus in anti‐amyloid drug design, whose efforts are so far being centered on single‐target approaches aimed at inhibiting amyloid aggregation. Chaperones, known to maintain proteostasis, hence represent interesting targets for the development of novel therapeutics owing to their potential protective role against protein misfolding diseases. In this minireview, research on nanoparticles that can either emulate or help molecular chaperones in recognizing and/or correcting protein misfolding is discussed. The nascent concept of “nanochaperone” may indeed set future directions towards the development of cost‐effective, disease‐modifying drugs to treat several currently fatal disorders.

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“… Chaperone‐mimicking NPs or “artificial chaperones” which mimic the structure and behavior of chaperones [10, 33] Chaperone‐aiding NPs or “chemical chaperones”, which have chaperone‐like functions by assisting (re)folding, stabilizing unfolded proteins, mediating degradation, and assisting protein assembly [10] …”

Section: Nanochaperones To Treat Misfolding Diseasesmentioning

confidence: 99%

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

Gámez

¹

,

Caballero

²

2020

View full text Add to dashboard Cite

The generation of highly organized amyloid fibrils is associated with a wide range of conformational pathologies, including primarily neurodegenerative diseases. Such disorders are characterized by misfolded proteins that lose their normal physiological roles and acquire toxicity. Recent findings suggest that proteostasis network impairment may be one of the causes leading to the accumulation and spread of amyloids. These observations are certainly contributing to a new focus in anti‐amyloid drug design, whose efforts are so far being centered on single‐target approaches aimed at inhibiting amyloid aggregation. Chaperones, known to maintain proteostasis, hence represent interesting targets for the development of novel therapeutics owing to their potential protective role against protein misfolding diseases. In this minireview, research on nanoparticles that can either emulate or help molecular chaperones in recognizing and/or correcting protein misfolding is discussed. The nascent concept of “nanochaperone” may indeed set future directions towards the development of cost‐effective, disease‐modifying drugs to treat several currently fatal disorders.

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“…In this regard, current research aims at finding and standardizing compounds and delivery means targeting as specifically as possible the pathogenic chaperone [82][83][84][85][86]. If the chaperonopathy is by defect, positive chaperonotherapy is indicated, consisting in chaperone gene or protein replacement, or the use of manufactured chaperoning structures [87][88][89]; or chaperone-protein functional boosting with chemical compounds, namely chemical chaperones similar to those utilized for restoring enzymatic activity in genetic enzymopathies [82,[90][91][92][93]. Other approaches include the use of harmless stressors to induce production of a chaperone responsive to them when it is below the physiological concentration; namely, in cases of chaperonopathy by defect of the quantitative type [94].…”

Section: Conclusion and Perspectives For The Futurementioning

confidence: 99%

Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies

Macario

¹

,

Macario

²

2019

The Journal of Pathology

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Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone-gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post-transcriptional mechanisms, e.g. post-translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural-functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation.The canonical functions of chaperones pertain to the maintenance of protein homeostasis, in essence protein-quality control; for example: assisting in the correct folding of nascent polypeptides, ushering polypeptides to their place of residence including through membranes, helping partially denatured

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Mimicking Molecular Chaperones to Regulate Protein Folding

Cited by 65 publications

References 85 publications

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies

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