Pharmacological chaperones for enzyme enhancement therapy in genetic diseases.

Pharmacological chaperone therapy (PCT) is a rather new approach consisting in targeting incorrectly folded proteins by small molecules, thus, facilitating the correct folding of the protein and inducing a recovery of its functionality. Many diseases result from mutations on specific genes; this patent review focuses on those pathologies where PCT has a potential application for enzymatic enhancement. Rare diseases are the main area where PCT has been applied and the most advanced compounds are aiming to cure lysosomal storage disorders such as Fabry, Pompe or Gaucher. Until now, most compounds used as pharmacological chaperones were based on substrate-like chemical structures but recently new nonsubstrate-like and non-inhibitory compounds have been disclosed for Gaucher and Pompe diseases. This initiates a new era for pharmacological chaperones with more diverse chemical structures and binding modes. This review covers the patents relating to enzyme enhancement on pharmacological chaperone therapy. Only an update is presented for Gaucher disease, where PCT is highly applied and recently reviewed.

[1]  Y. Sugiyama,et al.  Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2. , 2012, Bioorganic & medicinal chemistry.

[2]  S. Chung,et al.  Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-beta-glucosidase. , 2007, Biochemical pharmacology.

[3]  D. Lockhart,et al.  Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[4]  T. Wrodnigg,et al.  Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1-gangliosidosis and Morquio B disease , 2012, Journal of Inherited Metabolic Disease.

[5]  T. Butters,et al.  Potent aminocyclitol glucocerebrosidase inhibitors are subnanomolar pharmacological chaperones for treating gaucher disease. , 2012, Journal of medicinal chemistry.

[6]  M. Ferrer,et al.  Discovery of a novel noniminosugar acid α glucosidase chaperone series. , 2012, Journal of medicinal chemistry.

[7]  Michel Bouvier,et al.  Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. , 2005, Journal of the American Society of Nephrology : JASN.

[8]  S. Angers,et al.  Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. , 2000, The Journal of clinical investigation.

[9]  D. Lockhart,et al.  The pharmacological chaperone 1‐deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha‐glucosidase , 2009, Human mutation.

[10]  Kai Du,et al.  Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. , 2005, The Journal of clinical investigation.

[11]  L. Galietta,et al.  Development of Substituted Benzo[c]quinolizinium Compounds as Novel Activators of the Cystic Fibrosis Chloride Channel* , 1999, The Journal of Biological Chemistry.

[12]  P. Dawson,et al.  Palmitoyl:protein thioesterase (PPT1) inhibitors can act as pharmacological chaperones in infantile Batten disease. , 2010, Biochemical and biophysical research communications.

[13]  賢司 大金,et al.  フォールディング・トラフィッキング異常の修正作用を有するリガンドの創製 ～網膜色素変性症への応用を目指した変異型ロドプシンのフォールディングを促進するロドプシンリガンドの創製研究～ , 2011 .

[14]  Yoshiyuki Suzuki,et al.  Galactonojirimycin derivatives restore mutant human β-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse , 2001, Brain and Development.

[15]  Takatoshi Kubo,et al.  Therapeutic chaperone effect of N-octyl 4-epi-β-valienamine on murine G(M1)-gangliosidosis. , 2012, Molecular genetics and metabolism.

[16]  M. James,et al.  Crystal structure of β-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone. , 2011, Journal of medicinal chemistry.

[17]  T. Butters,et al.  Rational design and synthesis of highly potent pharmacological chaperones for treatment of N370S mutant Gaucher disease. , 2009, Journal of medicinal chemistry.

[18]  P. Conn,et al.  Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. , 2011, Advances in pharmacology.

[19]  Satoshi Ishii,et al.  Accelerated transport and maturation of lysosomal α–galactosidase A in Fabry lymphoblasts by an enzyme inhibitor , 1999, Nature Medicine.

[20]  M. Fitzgerald,et al.  In Vivo and in Vitro Examination of Stability of Primary Hyperoxaluria-associated Human Alanine:Glyoxylate Aminotransferase* , 2008, Journal of Biological Chemistry.

[21]  I. Pogozheva,et al.  Pharmacological Chaperones Restore Function to MC4R Mutants Responsible for Severe Early-Onset Obesity , 2010, Journal of Pharmacology and Experimental Therapeutics.

[22]  Noel Southall,et al.  High Throughput Screening for Small Molecule Therapy for Gaucher Disease Using Patient Tissue as the Source of Mutant Glucocerebrosidase , 2012, PloS one.

[23]  S. Chung,et al.  The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms , 2006, Proceedings of the National Academy of Sciences.

[24]  J. Flanagan,et al.  Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. , 2011, Assay and drug development technologies.

[25]  A. Pshezhetsky,et al.  Protein Misfolding as an Underlying Molecular Defect in Mucopolysaccharidosis III Type C , 2009, PloS one.

[26]  Noel Southall,et al.  Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase. , 2012, Journal of medicinal chemistry.

[27]  R. Desnick.  α-Galactosidase A deficiency. Fabry disease , 2001 .

[28]  Robert J. Desnick,et al.  Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. , 2001, The New England journal of medicine.

[29]  Seiichiro Ogawa,et al.  Chemical modification of the β-glucocerebrosidase inhibitor N-octyl-β-valienamine : synthesis and biological evaluation of 4-epimeric and 4-O-(β-D-galactopyranosyl) derivatives , 2002 .

[30]  lhealtlhy youin-g,et al.  Hospital for Sick Children , 1857, British medical journal.

[31]  S. Withers,et al.  Rapid assembly of a library of lipophilic iminosugars via the thiol-ene reaction yields promising pharmacological chaperones for the treatment of Gaucher disease. , 2012, Journal of medicinal chemistry.

[32]  S. Withers,et al.  Pharmacological Enhancement of β-Hexosaminidase Activity in Fibroblasts from Adult Tay-Sachs and Sandhoff Patients* , 2004, Journal of Biological Chemistry.

[33]  P. Britz‐McKibbin,et al.  Inhibitor screening of pharmacological chaperones for lysosomal β-glucocerebrosidase by capillary electrophoresis , 2011, Analytical and bioanalytical chemistry.

[34]  S. Withers,et al.  Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors , 2010, Beilstein journal of organic chemistry.

[35]  Noel Southall,et al.  Evaluation of 2-thioxo-2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidin-4(1H)-one analogues as GAA activators. , 2010, European journal of medicinal chemistry.

[36]  J. Clarke,et al.  An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants). , 2011, Molecular genetics and metabolism.

[37]  T. Butters,et al.  Polyhydroxylated bicyclic isoureas and guanidines are potent glucocerebrosidase inhibitors and nanomolar enzyme activity enhancers in Gaucher cells. , 2011, Journal of the American Chemical Society.

[38]  C. Scriver,et al.  The Metabolic and Molecular Bases of Inherited Disease, 8th Edition 2001 , 2001, Journal of Inherited Metabolic Disease.

[39]  R. Stevens,et al.  Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations , 2004, Human mutation.

[40]  T. Butters,et al.  Synthesis of N-substituted ε-hexonolactams as pharmacological chaperones for the treatment of N370S mutant Gaucher disease. , 2012, Organic & biomolecular chemistry.

[41]  S. Gersting,et al.  Novel pharmacological chaperones that correct phenylketonuria in mice. , 2012, Human molecular genetics.

[42]  J. M. Benito,et al.  Pharmacological chaperone therapy for Gaucher disease: a patent review , 2011, Expert opinion on therapeutic patents.

[43]  Christine E. Bear,et al.  A Chemical Corrector Modifies the Channel Function of F508del-CFTR , 2010, Molecular Pharmacology.

[44]  D. Lockhart,et al.  The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines , 2009, Journal of Inherited Metabolic Disease.

[45]  A. Reuser,et al.  Chemical chaperones improve transport and enhance stability of mutant alpha-glucosidases in glycogen storage disease type II. , 2007, Molecular genetics and metabolism.

[46]  Noel Southall,et al.  High Throughput Screening for Inhibitors of Alpha-Galactosidase , 2010, Current chemical genomics.

[47]  S. Withers,et al.  High-throughput screening for human lysosomal beta-N-Acetyl hexosaminidase inhibitors acting as pharmacological chaperones. , 2007, Chemistry & biology.

[48]  Yoshiyuki Suzuki,et al.  Fibroblast screening for chaperone therapy in β-galactosidosis , 2006, Brain and Development.

[49]  T. Stockley,et al.  Pyrimethamine as a Potential Pharmacological Chaperone for Late-onset Forms of GM2 Gangliosidosis* , 2007, Journal of Biological Chemistry.

[50]  G. Parenti.  Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics , 2009, EMBO molecular medicine.

[51]  D. Lockhart,et al.  The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[52]  R. Guerrini,et al.  The potential action of galactose as a "chemical chaperone": increase of beta galactosidase activity in fibroblasts from an adult GM1-gangliosidosis patient. , 2009, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[53]  F. Stratford,et al.  Benzo(c)quinolizinium drugs inhibit degradation of Delta F508-CFTR cytoplasmic domain. , 2003, Biochemical and biophysical research communications.

[54]  Canhui Li,et al.  A Small-Molecule Modulator Interacts Directly with ΔPhe508-CFTR to Modify Its ATPase Activity and Conformational Stability , 2009, Molecular Pharmacology.

[55]  James Rader,et al.  Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[56]  A. Velázquez‐Campoy,et al.  Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. , 2008, The Journal of clinical investigation.

[57]  Christopher P Austin,et al.  Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity. , 2011, Journal of medicinal chemistry.

[58]  S. Tuske,et al.  Isofagomine Induced Stabilization of Glucocerebrosidase , 2008, Chembiochem : a European journal of chemical biology.

[59]  A. Ballabio,et al.  Pharmacological Enhancement of Mutated α-Glucosidase Activity in Fibroblasts from Patients with Pompe Disease. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[60]  G. Murray,et al.  Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase. , 2008, Biochemical and biophysical research communications.

[61]  Giorgio Colombo,et al.  Pharmacological enhancement of α-glucosidase by the allosteric chaperone N-acetylcysteine. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[62]  P. Negulescu,et al.  Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809 , 2011, Proceedings of the National Academy of Sciences.

[63]  Seiichiro Ogawa,et al.  Chemical chaperone therapy for brain pathology in GM1-gangliosidosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[64]  M. Barone,et al.  The Pharmacological Chaperone N-butyldeoxynojirimycin Enhances Enzyme Replacement Therapy in Pompe Disease Fibroblasts , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[65]  C. Eckman,et al.  Molecular Characterization of Mutations That Cause Globoid Cell Leukodystrophy and Pharmacological Rescue Using Small Molecule Chemical Chaperones , 2010, The Journal of Neuroscience.

[66]  R. Dwek,et al.  Design, Synthesis, and Biological Evaluation of Enantiomeric β‐N‐Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay‐Sachs and Sandhoff Disease , 2009, ChemMedChem.

[67]  Satoshi Ishii,et al.  Galactose stabilizes various missense mutants of α-galactosidase in Fabry disease , 1995 .

[68]  G. Schitter,et al.  DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts. , 2010, Molecular genetics and metabolism.

[69]  Fred E. Cohen,et al.  Therapeutic approaches to protein-misfolding diseases , 2003, Nature.

[70]  Douglas R Martin,et al.  Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy. , 2012, Molecular genetics and metabolism.

[71]  D. Lockhart,et al.  The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of β‐glucosidase , 2010, The FEBS journal.

[72]  S. Withers,et al.  Fluorous Iminoalditols: A New Family of Glycosidase Inhibitors and Pharmacological Chaperones , 2010, Chembiochem : a European journal of chemical biology.