Small molecule pharmacological chaperones: From thermodynamic stabilization to pharmaceutical drugs

被引:112
作者
Arakawa, Tsutomu
Ejima, Daisuke
Kita, Yoshiko
Tsumoto, Kouhei [1 ]
机构
[1] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Kashiwa, Chiba 2778562, Japan
[2] Alliance Prot Labs, Thousand Oaks, CA 91360 USA
[3] Ajinomoto Inc, Dept Appl Res, Amino Sci Labs, Kawasaki, Kanagawa, Japan
来源
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS | 2006年 / 1764卷 / 11期
关键词
pharmacological chaperone; chemical chaperone; osmolyte; stabilization;
D O I
10.1016/j.bbapap.2006.08.012
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A great deal of attention has been paid to so-called amyloid diseases, in which the proteins responsible for the cell death and resultant diseases undergo conformational changes and aggregate in vivo, although whether aggregate formation is the cause or the result of the cell death is controversial. Recently, an increasing attention is given to protein folding diseases tightly associated with mutations. These mutations result in temperature-dependent misfolding and hence inactivation of the proteins, leading to loss of function, at physiological temperature; at low so-called permissive temperatures, the mutant proteins correctly fold and acquire functional structure. Alternatively, activation can be induced by use of osmolytes, which restores the folding of the mutant proteins and hence are called chemical chaperones. The osmolytes are compatible with macromolecular function and do stabilize the native protein structure. However, chemical chaperones require high concentrations for effective folding of mutant proteins and hence are too toxic in in-vivo applications. This limitation can be overcome by pharmacological chaperones, whose functions are similar to the chemical chaperones, but occur at much lower concentrations, i.e., physiologically acceptable concentrations. Although the research and clinical importance of pharmacological chaperones has been emphasized, the initial and central concept of osmolytes is largely ignored. Here we attempt to bridge the concept of osmolytes to applications of pharmacological chaperones. (c) 2006 Elsevier B.V. All rights reserved.
引用
收藏
页码:1677 / 1687
页数:11
相关论文
共 135 条
[1]   Neurotrophic factors in Huntington's disease [J].
Alberch, J ;
Pérez-Navarro, E ;
Canals, JM .
NGF AND RELATED MOLECULES IN HEALTH AND DISEASE, 2004, 146 :195-229
[2]  
[Anonymous], 1971, DIMETHYL SULFOXIDE
[3]   PREFERENTIAL INTERACTIONS OF PROTEINS WITH SOLVENT COMPONENTS IN AQUEOUS AMINO-ACID SOLUTIONS [J].
ARAKAWA, T ;
TIMASHEFF, SN .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1983, 224 (01) :169-177
[4]   PROTEIN STABILIZATION AND DESTABILIZATION BY GUANIDINIUM SALTS [J].
ARAKAWA, T ;
TIMASHEFF, SN .
BIOCHEMISTRY, 1984, 23 (25) :5924-5929
[5]  
ARAKAWA T, 1984, J BIOL CHEM, V259, P4979
[6]   STABILIZATION OF PROTEIN-STRUCTURE BY SUGARS [J].
ARAKAWA, T ;
TIMASHEFF, SN .
BIOCHEMISTRY, 1982, 21 (25) :6536-6544
[7]   THE STABILIZATION OF PROTEINS BY OSMOLYTES [J].
ARAKAWA, T ;
TIMASHEFF, SN .
BIOPHYSICAL JOURNAL, 1985, 47 (03) :411-414
[8]   PREFERENTIAL INTERACTIONS OF PROTEINS WITH SALTS IN CONCENTRATED-SOLUTIONS [J].
ARAKAWA, T ;
TIMASHEFF, SN .
BIOCHEMISTRY, 1982, 21 (25) :6545-6552
[9]   Integration of endoplasmic reticulum signaling in health and disease [J].
Aridor, M ;
Balch, WE .
NATURE MEDICINE, 1999, 5 (07) :745-751
[10]   INCREASED THERMAL-STABILITY OF PROTEINS IN THE PRESENCE OF SUGARS AND POLYOLS [J].
BACK, JF ;
OAKENFULL, D ;
SMITH, MB .
BIOCHEMISTRY, 1979, 18 (23) :5191-5196