Abstract
An increasing number of studies indicate that low-molecular-weight compounds can help correct conformational diseases by inhibiting the aggregation or enable the mutant proteins to escape the quality control systems, and thus their function can be rescued. The small molecules were named chemical chaperones and it is thought that they nonselectively stabilize the mutant proteins and facilitate their folding. Chemical chaperones are usually osmotically active, such as DMSO, glycerol, or deuterated water, but other compounds, such as 4-phenylbutiric acid, are also members of the chemical chaperone group. More recently, compounds such as receptor ligands or enzyme inhibitors, which selectively recognize the mutant proteins, were also found to rescue conformational mutants and were termed pharmacological chaperones. An increasing amount of evidence suggests that the action of pharmacological chaperones could be generalized to a large number of misfolded proteins, representing new therapeutic possibilties for the treatment of conformational diseases. A new and exciting strategy has recently been developed, leading to the new chemical group called folding agonist. These smallmolecules are designed to bind proteins and thus restore their native conformation.
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References
Baskakov IV, Kumar R, Srinivasan G, Ji YS, Bolen DW, Thompson EB (1999) Trimethylamine N-oxide-induced cooperative folding of an intrinsically unfolded transcription-activating fragment of human glucocorticoid receptor. J Biol Chem 274:10693–10696
Bebok Z, Venglarik CJ, Panczel Z, Jilling T, Kirk KL, Sorscher EJ (1998) Activation of Delta F508 CFTR in an epithelial monolayer. Am J Physiol 275:599–607
Bernier V, Lagace M, Bichet DG, Bouvier M (2004) Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 15:222–228
Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ (1996) Chemical chaperones correct the mutant phenotype of the DF508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1:117–125
Brown CR, Hong-Brown LQ, Welch WJ (1997) Correcting temperature-sensitive protein folding defects. J Clin Invest 99:1432–1444
Burrows JA, Willis LK, Perlmutter DH (2000) Chemical chaperones mediate increased secretion of mutant a1-antitrypsin (a1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in a1-AT deficiency. Proc Natl Acad Sci U S A 97:1796–1801
Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev 16:2743–2748
Chilson OP, Chilson AE (2003) Perturbation of folding and reassociation of lactate dehydrogenase by proline and trimethylamine oxide. Appl Environm Microbiol 69:6527–6532
Cohen FE, Kelly JW (2003) Therapeutic approaches to protein misfolding diseases. Nature 426:905–909
Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ (1995) Oral sodium phenylbutyrate therapy in homozygous beta thalassemia: a clinical trial. Blood 85:43–49
Conn PM, Leanos-Miranda A, Janovick JA (2002) Protein origami: therapeutic rescue of misfolded gene products. Mol Intervent 2:308–316
Csonka LN (1989) Physical and genetic responses of bacteria to osmotic stress. Microbiol Rev 53:121–147
Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803
De Fost M, Aerts JM, Hollak CE (2003) Gaucher disease: from fundamental research to effective therapeutic interventions. Neth J Med 61:3–8
Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ (1992) Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358:761–764
Diamant S, Eliahu N, Rosenthal D, Goloubinoff P (2001) Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J Biol Chem 276:39586–39591
Dormer RL, Derand R, McNeilly CM, Mettey Y, Bulteau-Pignoux L, Metaye T, Vierfond JM, Gray MA, Galietta LJ, Morris MR, Pereira MM, Doull IJ, Becq F, McPherson MA (2001) Correction of delF508-CFTR activity with benzo(c)quinolizinium compounds through facilitation of its processing in cystic fibrosis airway cells. J Cell Sci 114:4073–4081
Daugherty DL, Rozema D, Hanson PE, Gellman SH (1998) Artificial chaperone-assisted refolding of citrate synthase. J Biol Chem 273:33961–33971
Fan JQ, Ishii S, Asano N, Suzuki Y (1999) Accelerated transport and maturation of lysosomal a-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 5:112–115
Friedler A, DeDecker BS, Freund SM, Blair C, Rudiger S, Fersht AR (2004) Structural distortion of p53 by the mutation R249S and its rescue by adesigned peptide: implications for “mutant conformation”. J Mol Biol 336:187–196
Frustaci A, Chimenti C, Ricci R, Natale L, Russo MA, Pieroni M, Eng CM, Desnick RJ (2001) Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med 345:25–32
Foster BA, Coffey HA, Morin MJ, Rastinejad F (1999) Pharmacological rescue of mutant p53 conformation and function. Science 286:2507–2510
Gu Y, Singh N (2004) Doxycycline and protein folding agents rescue the abnormal phenotype of familial CJD H187R in a cell model. Brain Res Mol Brain Res 123:37–44
Ghumman B, Bertram EM, Watts TH (1998) Chemical chaperones enhance superantigen and conventional antigen presentation by HLA-DM-deficient as well as HLA-DM-sufficient antigen-presenting cells and enhance IgG2a production in vivo. J Immunol 161:3262–3270
Galietta LJ, Springsteel MF, Eda M, Niedzinski EJ, By K, Haddadin MJ, Kurth MJ, Nantz MH, Verkman AS (2001) Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds. J Biol Chem 276:19723–19728
Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR, Selivanova G (2003) Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide. Proc Natl Acad Sci U S A 100:13303–13307
Janovick JA, Maya-Nunez G, Conn PM (2002) Rescue of hypogonadotropic hypogonadism causing and manufactured GnRH receptor mutants by a specific protein-folding template: misrouted proteins as a novel disease etiology and therapeutic target. J Clin Endocrinol Metab 87:3255–3262
Kaler SG (1998) Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. Am J Clin Nutr 67:1029–1034
Kern R, Joseleau-Petit D, Chattopadhyay MK, Richarme G (2001) Chaperone-like properties of lysophospholipids. Biochem Biophys Res Commun 289:1268–1274
Kim BE, Smith K, Meagher CK, Petris MJ (2002) A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation. J Biol Chem 277:44079–44084
Kopito RR (1999) Biosynthesis and degradation of CFTR. Physiol Rev 79:167–173
Kopito RR, Ron D (2000) Conformational disease. Nat Cell Biol 2:207–209
Korth C, May BC, Cohen FE, Prusiner SB (2001) Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A 98:9836–9841
Krause M, Rudolph R, Schwarz E (2002) The non-ionic detergent Brij 58P mimics chaperone effects. FEBS Lett 532:253–255
Loo TW, Clarke DM (1994) Prolonged association of temperature sensitive mutants of human P-glycoprotein with calnexin during biogenesis. J Biol Chem 269:28683–28689
Loo TW, Clarke DM (1995) P-glycoprotein. Associations between domains and between domains and molecular chaperones. J Biol Chem 270:21839–21844
Loo TW, Clarke DM (1999) Determining the structure and mechanism of the human multidrug resistance P-glycoprotein using cysteine-scanning mutagenesis and thiol-modification techniques. Biochim Biophys Acta 1461:315–325
Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, Itoh M, Matsuzaki Y, Yasuda Y, Ogawa S, Sakata Y, Nanba E, Higaki K, Ogawa Y, Tominaga L, Ohno K, Iwasaki H, Watanabe H, Brady RO, Suzuki Y (2003) Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis. Proc Natl Acad Sci U S A 100: 15912–15917
Morello JP, Bichet DG (2001) Nephrogenic diabetes insipidus. Annu Rev Physiol 63:607–630
Morello JP, Petaja-Repo UE, Bichet DG, Bouvier M (2000a) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21:466–469
Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, Bouvier M (2000b) Pharmacological chaperones rescue cell surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105:887–895
Needham M, Stockley RA (2004) Alpha 1-antitrypsin deficiency. 3: Clinical manifestations and natural history. Thorax 59:441–445
Okumiya T, Ishii S, Takenaka T, Kase R, Kamei S, Sakuraba H, Suzuki Y (1995) Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease. Biochem Biophys Res Commun 214:1219–1224
Partridge CJ, Beech DJ, Sivaprasadarao A (2001) Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J Biol Chem 276:35947–35952
Petaja-Repo UE, Hogue M, Bhalla S, Laperriere A, Morello JP, Bouvier M (2002) Ligands act as pharmacological chaperones and increase the efficiency of d opioid receptor maturation. EMBO J 21:1628–1637
Qi X, Hosoi T, Okuma Y, Kaneko M, Nomura Y (2004) Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol 66:899–908
Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR (1996) Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 271:635–638
Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW (2002) Chemical chaperones increase the cellular activity of N370S b-glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci U S A 99: 15428–15433
Selkoe DJ (2003) Folding proteins in fatal ways. Nature 426:900–904
Sitia R, Braakman I (2003) Quality control in the endoplasmic reticulum protein factory. Nature 426: 891–894
Smith DF, Whitesell L, Katsanis E (1998) Molecular chaperones: biology and prospects for pharmacological intervention. Pharmacol Rev 50:493–514
Song JL, Chuang DT (2001) Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chain a-ketoacid decarboxylase in maple syrup urine disease. J Biol Chem 276:40241–40246
Soto C (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4: 49–60
Soto C, Kascsak RJ, Saborio GP, Aucouturier P, Wisniewski T, Prelli F, Kascsak R, Mendez E, Harris DA, Ironside J, Tagliavini F, Carp RI, Frangione B (2000) Reversion of prion protein conformational changes by synthetic ß-sheet breaker peptides. Lancet 355:192–197
Tamarappoo BK, Verkman AS (1998) Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 101:2257–2267
Tamarappoo BK, Yang B, Verkman AS (1999) Misfolding of mutant aquaporin-2 water channels in nephrogenic diabetes insipidus. J Biol Chem 274:34825–34831
Tan CM, Nickols HH, Limbird LE (2003) Appropriate polarization following pharmacological rescue of v2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation. J Biol Chem 278:35678–35686
Wang W, Rastinejad F, El-Deiry WS (2003) Restoring p53-dependent tumor suppression. Cancer Biol Ther 2: 55–63
Welch WJ, Brown CR (1996) Influence of molecular and chemical chaperones on protein folding. Cell Stress Chaperones 1:109–115
Wiens GD, O’Hare T, Rittenberg MB (2001) Recovering antibody secretion using a hapten ligand as a chemical chaperone. J Biol Chem 276:40933–40939
Wright JM, Zeitlin PL, Cebotaru L, Guggino SE, Guggino WB (2004) Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics 16:204–211
Zeitlin PL, Diener-West M, Rubenstein RC, Boyle MP, Lee CK, Brass-Ernst L (2002) Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol Ther 6:119–126
Zhou Z, Gong Q, January CT (1999) Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem 274:31123–31126
Yan F, Lin CW, Weisiger E, Cartier EA, Taschenberger G, Shyng SL (2004) Sulfonylureas correct trafficking defects of ATP-sensitive potassium channels caused by mutations in the sulfonylurea receptor. J Biol Chem 279: 11096–11105
Yang DS, Yip CM, Huang THJ, Chakrabartty A, Fraser PE (1999) Manipulating the amyloid beta aggregation pathway with chemical chaperones. J Biol Chem 274:32970–32974
Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (2002) Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 10:88–99
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Papp, E., Csermely, P. (2006). Chemical Chaperones: Mechanisms of Action and Potential Use. In: Starke, K., Gaestel, M. (eds) Molecular Chaperones in Health and Disease. Handbook of Experimental Pharmacology, vol 172. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29717-0_16
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DOI: https://doi.org/10.1007/3-540-29717-0_16
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