Chemical chaperone

A number of different low molecular weight compounds are known to stablize proteins in their native conformation and, therefore, may be effective in correcting of protein folding abnormalities in vivo. Relevant compounds are iV-acetyl-L-lysine, L-camitine, taurine, betaine, ectoine, and hydroxy-ectoine [4]. Some of these chemical chaperones and pharmacological chaperones are already used in clinical trials to combat protein folding diseases, such as cystic fibrosis. 

Welch W, Brown CR (1996) Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1 109-115... 

Papp E, Csermely P (2006) Chemical chaperones mechanisms of action and potential use. Handb. Exp. Pharmacol. 172 405-l 6... 

Cheese Reaction Chemical Chaperone Chemical Library Chemical Neurotransmission Chemoattractant Receptors Chemokine Receptors Chemokines... 

Martirosova, E., Karpekina, T., El -Registan, G. Enzyme modification by natural chemical chaperons of microorganisms. Microbiology, Vol.73, No.5, (August 2004), pp. 609-615, ISSN 1350-0872... 

Matsuda, J., Suzuki, O., Oshima, A. et al. Chemical chaperone therapy for brain pathology in GM1-gangliosidosis. Proc. Natl Acad. Sci. U.S.A. 100 15912-15917,2003. 

B. Brumshtein, H. M. Greenblatt, T. D. Butters, Y. Shaaltiel, D. Aviezer, I. Sihnan, A. H. Futerman, and J. L. Sussman, Crystal structures of complexes of iV-butyl- and iV-nonyl-deoxynojirimycin bound to acid P-glucosidase. Insights into the mechanism of chemical chaperone action in Gaucher disease,... 

A. R. Sawkar, S. L. Adamski-Wemer, W.-C. Cheng, C.-H. Wong, E. Beutler, K.-P. Zimmer, and J. W. Kelly, Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles, Chem. Biol., 12 (2005) 1235-1244. 

Prenatal diagnosis is available for all the sphingolipidoses. This makes an early and reliable diagnosis of the utmost importance. For many of the sphingolipidoses, symptomatic treatment in the form of bone marrow transplantation, enzyme replacement therapy, substrate reduction therapy, or chemical chaperone therapy is... 

Sawkar, A. R., Cheng, W. C., Beutler, E., Wong, C. H., Balch, W. E. and Kelly, J. W. (2002). Chemical chaperones increase the cellular activity of N370S beta-glucosidase A therapeutic strategy for Gaucher disease. Proc. Natl. Acad. Sci. USA 99, 15428-15433. 

As discussed earlier in this chapter and also in chapter 6, thermal stabilities of proteins in vivo are influenced by many constituents of the intracellular milieu, including low-molecular-mass protein stabilizers. The process of protein folding, whether during initial synthesis or following heat-induced unfolding, thus will be influenced not only by activities of protein chaperones, but also by the activities of low-mole-cular-mass organic solutes. In principle, heat stress could be ameliorated in part by accumulation of low-molecular-mass protein-stabilizing solutes that favor formation of the compact, folded state of proteins. Such chemical chaperones could complement the activities of protein chaperones. 

Trehalose is able to stabilize biological structures in a dehydrated form, and to make them intact and functional as soon as the hydration and temperature conditions return to normal. Thus, it behaves as a chemical chaperone in desiccation stress. Additionally, trehalose acts as a protectant against other environmental stresses such as freezing [4,5], osmotic shock [6], oxidation [7-9],... 

Several studies since then have supported this suggestion, and now it is widely accepted that conformational change/structural perturbation is a prerequisite for amyloid formation. Structural perturbation involves destabilization of the native state, thus forming nonnative states or partially unfolded intermediates (kinetic or thermodynamic intermediates), which are prone to aggregation. Mild to harsh conditions such as low pH, exposure to elevated temperatures, exposure to hydrophobic surfaces and partial denaturation using urea and guanidinium chloride are used to achieve nonnative states. Stabilizers of intermediate states such as trimethylamine N-oxide (TMAO) are also used for amyloidogenesis. However, natively unfolded proteins, such as a-synuclein, tau protein and yeast prion, require some structural stabilization for the formation of partially folded intermediates that are competent for fibril formation. Conditions for partial structural consolidation include low pH, presence of sodium dodecyl sulfate (SDS), temperature or chemical chaperones. 

The term chemical chaperone has been proposed to describe small molecules such as glycerol, dimethylsulfoxide, and trimethylamine N-oxide that act as protein-stabilizing agents. This terminology is unfortunate and confuses students, because proteins are also chemicals. This term should be replaced by the term kosmotrope that physical chemists use to describe small molecules that stabilise proteins. 

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