title: Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders.
abstract: Many human diseases result from mutations in specific genes. Once translated, the resulting aberrant proteins may be functionally competent and produced at near-normal levels. However, because of the mutations, the proteins are recognized by the quality control system of the endoplasmic reticulum and are not processed or trafficked correctly, ultimately leading to cellular dysfunction and disease. Pharmacological chaperones (PCs) are small molecules designed to mitigate this problem by selectively binding and stabilizing their target protein, thus reducing premature degradation, facilitating intracellular trafficking, and increasing cellular activity. Partial or complete restoration of normal function by PCs has been shown for numerous types of mutant proteins, including secreted proteins, transcription factors, ion channels, G protein-coupled receptors, and, importantly, lysosomal enzymes. Collectively, lysosomal storage disorders (LSDs) result from genetic mutations in the genes that encode specific lysosomal enzymes, leading to a deficiency in essential enzymatic activity and cellular accumulation of the respective substrate. To date, over 50 different LSDs have been identified, several of which are treated clinically with enzyme replacement therapy or substrate reduction therapy, although insufficiently in some cases. Importantly, a wide range of in vitro assays are now available to measure mutant lysosomal enzyme interaction with and stabilization by PCs, as well as subsequent increases in cellular enzyme levels and function. The application of these assays to the identification and characterization of candidate PCs for mutant lysosomal enzymes will be discussed in this review. In addition, considerations for the successful in vivo use and development of PCs to treat LSDs will be discussed.
authors: Amicus Therapeutics, Cranbury, New Jersey. kvalenzano@amicustherapeutics.com
authors: Kenneth J
authors: KJ
authors: Valenzano
authors: Richie
authors: R
authors: Khanna
authors: Allan C
authors: AC
authors: Powe
authors: Robert
authors: R
authors: Boyd
authors: Gary
authors: G
authors: Lee
authors: John J
authors: JJ
authors: Flanagan
authors: Elfrida R
authors: ER
authors: Benjamin
references: J Biomol Tech. 2003 Sep;14(3):171-82
references: 13678147
references: Pediatrics. 2009 Jan;123(1):229-40
references: 19117887
references: Pharmacol Rev. 2007 Sep;59(3):225-50
references: 17878512
references: FASEB J. 1987 Dec;1(6):462-8
references: 3315809
references: J Lipid Res. 1994 Aug;35(8):1441-51
references: 7989868
references: J Biol Chem. 1996 Nov 1;271(44):27259-65
references: 8910299
references: J Biol Chem. 1991 Nov 15;266(32):21327-30
references: 1939168
references: Neuromuscul Disord. 2005 Jan;15(1):24-31
references: 15639117
references: Hum Mol Genet. 2005 Aug 15;14(16):2387-98
references: 16000318
references: Curr Opin Investig Drugs. 2010 Oct;11(10):1169-81
references: 20872320
references: J Biol Chem. 1980 May 25;255(10):4946-50
references: 6989822
references: J Biochem. 1994 Jan;115(1):113-9
references: 8188616
references: FEBS J. 2006 Sep;273(17):4082-92
references: 16934036
references: N Engl J Med. 1992 Dec 3;327(23):1632-6
references: 1435900
references: Eur J Biochem. 1984 Mar 15;139(3):497-502
references: 6365554
references: J Biochem. 2011 Feb;149(2):161-70
references: 20961863
references: Bioorg Med Chem. 2006 Dec 1;14(23):7736-44
references: 16919960
references: J Biol Chem. 1998 Jul 24;273(30):19086-92
references: 9668092
references: Int J Clin Pharmacol Ther. 2009;47 Suppl 1:S111-7
references: 20040321
references: J Eur Acad Dermatol Venereol. 2008 Jun;22(6):692-5
references: 18384565
references: Nat Med. 1999 Jan;5(1):112-5
references: 9883849
references: J Inherit Metab Dis. 2011 Feb;34(1):209-15
references: 20978939
references: Glycobiology. 2010 Mar;20(3):356-65
references: 19917668
references: Ann Neurol. 2008 Nov;64(5):514-22
references: 19067373
references: J Inherit Metab Dis. 2009 Jun;32(3):424-40
references: 19387866
references: Mol Ther. 2010 Jan;18(1):23-33
references: 19773742
references: Ther Clin Risk Manag. 2009;5:767-72
references: 19816575
references: Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):8861-6
references: 10430861
references: Mol Genet Metab. 2010 Apr;99(4):351-7
references: 20045366
references: Anal Biochem. 2004 Nov 15;334(2):227-33
references: 15494128
references: Curr Mol Med. 2002 Mar;2(2):145-66
references: 11949932
references: ACS Chem Biol. 2006 May 23;1(4):235-51
references: 17163678
references: Clin Sci (Lond). 1979 Sep;57(3):265-72
references: 38945
references: J Med Chem. 2009 May 28;52(10):3146-9
references: 19397268
references: Nat Chem Biol. 2007 Feb;3(2):101-7
references: 17187079
references: Genet Test. 1997;1(1):5-12
references: 10464619
references: Dev Neurosci. 1983-1984;6(1):58-71
references: 6421563
references: Biochim Biophys Acta. 2004 Nov 5;1690(3):250-7
references: 15511632
references: Pediatrics. 2007 Jul;120(1):e37-46
references: 17606547
references: Am J Hum Genet. 2001 Mar;68(3):711-22
references: 11179018
references: Clin Chim Acta. 2010 Nov 11;411(21-22):1666-70
references: 20599861
references: Biochim Biophys Acta. 1999 Oct 8;1455(2-3):105-38
references: 10571007
references: J Biol Chem. 2010 Feb 5;285(6):3625-3632
references: 19940122
references: J Pediatr. 2009 Aug;155(2):271-5.e2
references: 19486996
references: ChemMedChem. 2009 Mar;4(3):378-92
references: 19145603
references: Mol Genet Metab. 2010 Dec;101(4):338-45
references: 20826098
references: Exp Mol Med. 2009 Jan 31;41(1):1-7
references: 19287194
references: J Lipid Res. 2010 Sep;51(9):2808-17
references: 20526001
references: J Biol Chem. 2009 Aug 28;284(35):23502-16
references: 19578116
references: Blood Cells Mol Dis. 2009 Mar-Apr;42(2):159-66
references: 19167250
references: Mol Genet Metab. 2010 Jan;99(1):26-33
references: 19775921
references: Blood. 1997 May 1;89(9):3412-20
references: 9129049
references: Mol Genet Metab. 2008 Aug;94(4):469-475
references: 18502162
references: Mol Genet Metab. 2009 Jan;96(1):4-12
references: 19022694
references: Hum Mutat. 2008 Feb;29(2):331
references: 18205205
references: Brain Dev. 2001 Aug;23(5):284-7
references: 11504597
references: J Pharmacol Exp Ther. 2009 Mar;328(3):723-31
references: 19106170
references: J Cell Biol. 1988 Dec;107(6 Pt 1):2097-107
references: 3143734
references: J Inherit Metab Dis. 1999 Jun;22(5):623-37
references: 10399095
references: Hum Mol Genet. 2008 Feb 15;17(4):469-77
references: 17989065
references: Mol Genet Metab. 2007 Mar;90(3):329-37
references: 17185020
references: Biochem Biophys Res Commun. 2007 Jul 20;359(1):168-73
references: 17532296
references: Hum Mutat. 2011 Aug;32(8):965-77
references: 21598360
references: Trends Cell Biol. 2001 Jul;11(7):294-7
references: 11413040
references: Eur J Med Chem. 2010 May;45(5):1880-97
references: 20206419
references: Mol Ther. 2007 Mar;15(3):508-514
references: 28182897
references: FEBS J. 2006 Apr;273(7):1331-49
references: 16689923
references: Annu Rev Biochem. 1985;54:631-64
references: 3896128
references: Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13813-8
references: 16945909
references: Klin Monbl Augenheilkd. 2011 Feb;228(2):144-60
references: 20309790
references: Glycobiology. 2000 Dec;10(12):1249-58
references: 11159916
references: Bioorg Med Chem. 2010 Jun 1;18(11):3790-4
references: 20457528
references: Philos Trans R Soc Lond B Biol Sci. 2003 May 29;358(1433):961-6
references: 12803930
references: J Biol Chem. 2005 Feb 25;280(8):6780-91
references: 15520017
references: Mol Genet Metab. 2010 Dec;101(4):364-9
references: 20826101
references: N Engl J Med. 1975 Jan 9;292(2):61-3
references: 1109441
references: Chembiochem. 2010 Sep 24;11(14):2026-33
references: 20715263
references: Biochem Biophys Res Commun. 2010 Apr 23;395(1):66-9
references: 20346914
references: FEBS Lett. 1997 Jun 9;409(2):115-20
references: 9202129
references: J Clin Invest. 2002 May;109(9):1215-21
references: 11994410
references: Chem Biol. 2007 Feb;14(2):153-64
references: 17317569
references: Bioorg Med Chem. 2004 Mar 1;12(5):995-1002
references: 14980612
references: Pediatrics. 2009 Apr;123(4):1191-207
references: 19336380
references: Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2503-8
references: 9482915
references: Mol Genet Metab. 2009 Nov;98(3):319-21
references: 19640753
references: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15428-33
references: 12434014
references: Am J Hum Genet. 1977 Mar;29(2):191-4
references: 15452
references: Mol Genet Metab. 2008 Sep-Oct;95(1-2):59-65
references: 18693054
references: Ann Neurol. 2007 Dec;62(6):671-5
references: 17994547
references: Br J Pharmacol. 2007 Sep;152(1):62-71
references: 17603554
references: Biochim Biophys Acta. 1993 Sep 29;1170(1):72-9
references: 8399329
references: Hum Genet. 2007 Mar;121(1):1-22
references: 17089160
references: J Lipid Res. 2005 Oct;46(10):2102-13
references: 16061944
references: N Engl J Med. 2001 Jul 5;345(1):25-32
references: 11439944
references: Methods Cell Biol. 1975;9(0):13-23
references: 1134381
references: Nat Protoc. 2007;2(9):2212-21
references: 17853878
references: Mol Genet Metab. 2011 Jan;102(1):6-12
references: 20926324
references: J Biol Chem. 2004 Apr 2;279(14):13478-87
references: 14724290
references: Am J Hum Genet. 1983 Sep;35(5):900-13
references: 6614006
references: IUBMB Life. 2010 Jan;62(1):33-40
references: 20014233
references: EMBO J. 2008 Jan 23;27(2):315-27
references: 18216874
references: J Biol. 2009 Oct 13;8(9):80
references: 19833004
references: Chemistry. 2002 Mar 1;8(5):1218-26
references: 11891910
references: JAMA. 2001 Jun 6;285(21):2743-9
references: 11386930
references: Am J Hum Genet. 1971 Jan;23(1):62-6
references: 5581982
references: Biochim Biophys Acta. 2011 Jan;1812(1):70-6
references: 20851180
references: Biochim Biophys Acta. 2004 Aug 4;1689(3):219-28
references: 15276648
references: Perspect Medicin Chem. 2009 May 26;3:7-19
references: 19812739
references: Chembiochem. 2009 Nov 23;10(17):2780-92
references: 19830760
references: PLoS Biol. 2008 Feb;6(2):e26
references: 18254660
references: J Cell Physiol. 1988 Dec;137(3):411-20
references: 3192622
references: Am J Pathol. 2003 Nov;163(5):2093-101
references: 14578207
references: J Biol Chem. 2007 Mar 23;282(12):9150-61
references: 17237499
references: Chem Phys Lipids. 1994 Aug 8;72(2):143-52
references: 7954976
references: Angew Chem Int Ed Engl. 2005 Dec 1;44(45):7450-3
references: 16231389
references: Mol Genet Metab. 2010 Jul;100(3):262-8
references: 20409738
references: Physiology (Bethesda). 2010 Apr;25(2):102-15
references: 20430954
references: J Pediatr. 2006 Apr;148(4):533-539
references: 16647419
references: J Inherit Metab Dis. 2001 Apr;24(2):275-90
references: 11405346
references: Clin Genet. 1976 May;9(5):540-3
references: 1269177
references: Anal Biochem. 1999 May 1;269(2):410-7
references: 10222018
references: Arch Biochem Biophys. 1983 Jul 1;224(1):186-95
references: 6307147
references: ChemMedChem. 2011 Feb 7;6(2):353-61
references: 21275057
references: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13192-7
references: 17670938
references: Pediatr Ann. 2009 Aug;38(8):448-55
references: 19725195
references: EMBO Mol Med. 2009 Aug;1(5):268-79
references: 20049730
references: Hum Genet. 1992 Mar;88(5):513-23
references: 1348043
references: Eur J Paediatr Neurol. 2009 Mar;13(2):160-4
references: 18571950
references: FEBS J. 2010 Apr;277(7):1618-38
references: 20148966
references: Genet Med. 2008 May;10(5):353-8
references: 18496035
references: Biochemistry. 1983 Oct 25;22(22):5201-5
references: 6360205
references: Annu Rev Cell Dev Biol. 1998;14:19-57
references: 9891777
references: Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15835-40
references: 17035505
references: Genomics. 1996 May 1;33(3):457-62
references: 8661004
references: Blood Cells Mol Dis. 2003 Jan-Feb;30(1):97-9
references: 12667991
references: J Biol Chem. 1989 Feb 25;264(6):3380-4
references: 2521634
references: N Engl J Med. 1991 May 23;324(21):1464-70
references: 2023606
references: J Neurosci. 2010 Apr 21;30(16):5489-97
references: 20410102
references: Brain Dev. 2006 Sep;28(8):482-6
references: 16617000
references: J Biol Chem. 1987 Feb 15;262(5):2062-5
references: 3029062
references: Biochem Biophys Res Commun. 1995 Sep 25;214(3):1219-24
references: 7575533
references: Cell Biochem Funct. 1993 Sep;11(3):167-77
references: 8403230
references: Science. 2008 Jul 25;321(5888):569-72
references: 18653895
references: Glycobiology. 2001 Jan;11(1):99-103
references: 11181566
references: Chem Biol. 2005 Nov;12(11):1235-44
references: 16298303
references: Am J Physiol Cell Physiol. 2006 Apr;290(4):C1076-82
references: 16531566
references: Trends Biotechnol. 2010 May;28(5):237-45
references: 20346526
references: Annu Rev Biochem. 1991;60:257-80
references: 1883197
references: Br J Clin Pharmacol. 2009 Nov;68(5):765-9
references: 19917001
references: Biol Chem. 2008 Jan;389(1):1-11
references: 18095864
references: Pharmacogenet Genomics. 2008 Sep;18(9):773-80
references: 18698230
references: Carbohydr Res. 2010 Jul 2;345(10):1371-6
references: 20471633
references: Hum Genet. 1986 Aug;73(4):320-6
references: 3017841
references: PLoS One. 2009 Oct 13;4(10):e7434
references: 19823584
references: Acta Biochim Pol. 1999;46(2):303-14
references: 10547032
references: Anal Biochem. 1981 Apr;112(2):195-203
references: 6266278
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15912-7
references: 14676316
references: Mol Genet Metab. 2001 Jul;73(3):211-23
references: 11461188
references: Chembiochem. 2010 Nov 22;11(17):2453-64
references: 21064079
references: J Pediatr. 1976 Sep;89(3):438-40
references: 8599
references: Beilstein J Org Chem. 2010 Mar 01;6:21
references: 20502610
references: Mol Genet Metab. 2009 Jan;96(1):1-3
references: 19062323
references: Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350-4
references: 388439
references: Anal Biochem. 1997 May 1;247(2):268-71
references: 9177687
references: Hum Mutat. 2009 Dec;30(12):1683-92
references: 19862843
references: Lancet. 2000 Apr 29;355(9214):1481-5
references: 10801168
references: Biochemistry. 2009 Jun 9;48(22):4816-27
references: 19374450
references: Physiol Rev. 2007 Oct;87(4):1377-408
references: 17928587
references: Mol Genet Metab. 2009 Apr;96(4):225-32
references: 19167257
references: Muscle Nerve. 2003 Dec;28(6):703-10
references: 14639584
references: Glycobiology. 1999 Dec;9(12):1389-96
references: 10561464
references: Curr Opin Cell Biol. 2001 Aug;13(4):431-7
references: 11454449
references: J Am Soc Nephrol. 2009 May;20(5):1132-9
references: 19357250
references: J Biomol Screen. 2001 Dec;6(6):429-40
references: 11788061
references: Biochem J. 2007 Sep 1;406(2):285-95
references: 17555407
references: Chembiochem. 2008 Nov 3;9(16):2643-9
references: 18932186
references: J Biol Chem. 1993 Jan 25;268(3):2223-31
references: 8420990
references: FASEB J. 2005 Jan;19(1):12-8
references: 15629890
references: Chembiochem. 2008 Nov 3;9(16):2650-62
references: 18972510
references: J Comput Aided Mol Des. 2009 Aug;23(8):491-500
references: 19521672
references: Lab Invest. 2006 Dec;86(12):1208-20
references: 17075580
references: J Clin Invest. 1986 Jan;77(1):1-6
references: 3003148
references: Eur J Biochem. 2000 Jul;267(13):4179-86
references: 10866822
references: J Neurol. 2010 Jan;257(1):91-7
references: 19649685
references: Mol Genet Metab. 2007 Jan;90(1):49-57
references: 17095274
references: FEBS J. 2007 Oct;274(19):4951-61
references: 17894780
references: Nature. 2003 Dec 18;426(6968):900-4
references: 14685251