Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders

References

• Ellgaard L, Helenius A. ER quality control: towards an understanding at the molecular level. Curr Opin Cell Biol. 2001;13:431–437.
   PubMed Web of Science ®Google Scholar
• Ulloa-Aguirre A, Janovick JA, Brothers SP, et al. Pharmacologic rescue of conformationally-defective proteins: implications for the treatment of human disease. Traffic. 2004;5:821–837.
   PubMed Web of Science ®Google Scholar
• Tao YX, Conn PM. Pharmacoperones as novel therapeutics for diverse protein conformational diseases. Physiol Rev. 2018;98:697–725.
   PubMed Web of Science ®Google Scholar
• Conn PM, Ulloa-Aguirre A. Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv Pharmacol. 2011;62:109–141.
   PubMedGoogle Scholar
• Conn PM, Ulloa-Aguirre A, Janovick JA. “Pharmacoperone”: what’s in a word? Pharmacol Res. 2013;83:1–2.
   Google Scholar
• Leidenheimer NJ, Ryder KG. Pharmacological chaperoning: a primer on mechanism and pharmacology. Pharmacol Res. 2014;83:10–19.
   PubMed Web of Science ®Google Scholar
• Conn PM, Ulloa-Aguirre A. Trafficking of G-protein-coupled receptors to the plasma membrane: insights for pharmacoperone drugs. Trends Endocrinol Metab. 2010;21:190–197.
   PubMed Web of Science ®Google Scholar
• Tao YX, Conn PM. Chaperoning G protein-coupled receptors: from cell biology to therapeutics. Endocr Rev. 2014;35:602–647.
   PubMed Web of Science ®Google Scholar
• Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002;295:1852–1858.
   PubMed Web of Science ®Google Scholar
• Hendrick JP, Hartl FU. The role of molecular chaperones in protein folding. FASEB J. 1995;9:1559–1569.
   PubMed Web of Science ®Google Scholar
• Young JC, Agashe VR, Siegers K, et al. Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol. 2004;5:781–791.
   PubMed Web of Science ®Google Scholar
• Janovick JA, Brothers SP, Cornea A, et al. Refolding of misfolded mutant GPCR: post-translational pharmacoperone action in vitro. Mol Cell Endocrinol. 2007;272:77–85.
   PubMed Web of Science ®Google Scholar
• Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373:220–231.
   PubMed Web of Science ®Google Scholar
• Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del. N Engl J Med. 2017;377:2013–2023.
   PubMed Web of Science ®Google Scholar
• Ulloa-Aguirre A, Conn PM. Pharmacoperones as a new therapeutic approach: in vitro identification and in vivo validation of bioactive molecules. Curr Drug Targets. 2016;17:1471–1481.
   PubMed Web of Science ®Google Scholar
• Bernier V, Morello JP, Zarruk A, et al. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol. 2006;17:232–243.
   PubMed Web of Science ®Google Scholar
• Janovick JA, Stewart MD, Jacob D, et al. Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy. Proc Natl Acad Sci U S A. 2013;110:21030–21035.
   PubMed Web of Science ®Google Scholar
• Noorwez SM, Malhotra R, McDowell JH, et al. Retinoids assist the cellular folding of the autosomal dominant retinitis pigmentosa opsin mutant P23H. J Biol Chem. 2004;279:16278–16284.
   PubMed Web of Science ®Google Scholar
• Loo TW, Bartlett MC, Clarke DM. Rescue of folding defects in ABC transporters using pharmacological chaperones. J Bioenerg Biomembr. 2005;37:501–507.
   PubMed Web of Science ®Google Scholar
• Richter K, Haslbeck M, Buchner J. The heat shock response: life on the verge of death. Mol Cell. 2010;40:253–266.
   PubMed Web of Science ®Google Scholar
• Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–1086.
   PubMed Web of Science ®Google Scholar
• Kincaid MM, Cooper AA. ERADicate ER stress or die trying. Antioxid Redox Signal. 2007;9:2373–2387.
   PubMed Web of Science ®Google Scholar
• Nakatsukasa K, Brodsky JL. The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic. 2008;9:861–870.
   PubMed Web of Science ®Google Scholar
• Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol. 2004;14:20–28.
   PubMed Web of Science ®Google Scholar
• Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J Cell Biol. 2012;197:857–867.
   PubMed Web of Science ®Google Scholar
• Haynes CM, Titus EA, Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell. 2004;15:767–776.
   PubMed Web of Science ®Google Scholar
• Balch WE, Morimoto RI, Dillin A, et al. Adapting proteostasis for disease intervention. Science. 2008;319:916–919.
   PubMed Web of Science ®Google Scholar
• Wang YJ, Di XJ, Mu TW. Using pharmacological chaperones to restore proteostasis. Pharmacol Res. 2014;83:3–9.
   PubMed Web of Science ®Google Scholar
• Dobson CM. Principles of protein folding, misfolding and aggregation. Semin Cell Dev Biol. 2004;15:3–16.
   PubMed Web of Science ®Google Scholar
• Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature. 2011;475:324–332.
   PubMed Web of Science ®Google Scholar
• Duennwald ML, Echeverria A, Shorter J. Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. PLoS Biol. 2012;10:e1001346.
   PubMed Web of Science ®Google Scholar
• Gething MJ, Sambrook J. Protein folding in the cell. Nature. 1992;355:33–45.
   PubMed Web of Science ®Google Scholar
• Glover JR, Lindquist S. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell. 1998;94:73–82.
   PubMed Web of Science ®Google Scholar
• Hiller MM, Finger A, Schweiger M, et al. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science. 1996;273:1725–1728.
   PubMed Web of Science ®Google Scholar
• Schubert U, Anton LC, Gibbs J, et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature. 2000;404:770–774.
   PubMed Web of Science ®Google Scholar
• Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol. 2008;9:679–690.
   PubMed Web of Science ®Google Scholar
• Lievremont JP, Rizzuto R, Hendershot L, et al. BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca2+. J Biol Chem. 1997;272:30873–30879.
   PubMed Web of Science ®Google Scholar
• Hartl FU, Hayer-Hartl M. Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol. 2009;16:574–581.
   PubMed Web of Science ®Google Scholar
• Trombetta ES, Parodi AJ. Quality control and protein folding in the secretory pathway. Annu Rev Cell Dev Biol. 2003;19:649–676.
   PubMed Web of Science ®Google Scholar
• Robinson PJ, Pringle MA, Woolhead CA, et al. Folding of a single domain protein entering the endoplasmic reticulum precedes disulfide formation. J Biol Chem. 2017;292:6978–6986.
   PubMed Web of Science ®Google Scholar
• Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem. 2004;73:1019–1049.
   PubMed Web of Science ®Google Scholar
• Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006;125:443–451.
   PubMed Web of Science ®Google Scholar
• Chevet E, Cameron PH, Pelletier MF, et al. The endoplasmic reticulum: integration of protein folding, quality control, signaling and degradation. Curr Opin Struct Biol. 2001;11:120–124.
   PubMed Web of Science ®Google Scholar
• Ellgaard L, Helenius A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol. 2003;4:181–191.
   PubMed Web of Science ®Google Scholar
• Parodi AJ. Role of N-oligosaccharide endoplasmic reticulum processing reactions in glycoprotein folding and degradation. Biochem J. 2000;348(Pt 1):1–13.
   PubMedGoogle Scholar
• Schrag JD, Procopio DO, Cygler M, et al. Lectin control of protein folding and sorting in the secretory pathway. Trends Biochem Sci. 2003;28:49–57.
   PubMed Web of Science ®Google Scholar
• Williams DB. Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum. J Cell Sci. 2006;119:615–623.
   PubMed Web of Science ®Google Scholar
• Caramelo JJ, Parodi AJ. Getting in and out from calnexin/calreticulin cycles. J Biol Chem. 2008;283:10221–10225.
   PubMed Web of Science ®Google Scholar
• Kincaid MM, Cooper AA. Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals. Mol Biol Cell. 2007;18:455–463.
   PubMed Web of Science ®Google Scholar
• Briant K, Johnson N, Swanton E. Transmembrane domain quality control systems operate at the endoplasmic reticulum and Golgi apparatus. PLoS One. 2017;12:e0173924.
   PubMed Web of Science ®Google Scholar
• Dong C, Wu G. Regulation of anterograde transport of alpha2-adrenergic receptors by the N termini at multiple intracellular compartments. J Biol Chem. 2006;281:38543–38554.
   PubMed Web of Science ®Google Scholar
• Sato K, Nishikawa S, Nakano A. Membrane protein retrieval from the Golgi apparatus to the endoplasmic reticulum (ER): characterization of the RER1 gene product as a component involved in ER localization of Sec12p. Mol Biol Cell. 1995;6:1459–1477.
   PubMed Web of Science ®Google Scholar
• Arvan P, Zhao X, Ramos-Castaneda J, et al. Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems. Traffic. 2002;3:771–780.
   PubMed Web of Science ®Google Scholar
• Zhang X, Wang Y. Glycosylation quality control by the Golgi structure. J Mol Biol. 2016;428:3183–3193.
   PubMed Web of Science ®Google Scholar
• Okiyoneda T, Apaja PM, Lukacs GL. Protein quality control at the plasma membrane. Curr Opin Cell Biol. 2011;23:483–491.
   PubMed Web of Science ®Google Scholar
• Sharma M, Pampinella F, Nemes C, et al. Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes. J Cell Biol. 2004;164:923–933.
   PubMed Web of Science ®Google Scholar
• Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73:1251–1254.
   PubMed Web of Science ®Google Scholar
• Melo-Nava B, Casas-Gonzalez P, Perez-Solis MA, et al. Role of cysteine residues in the carboxyl-terminus of the follicle-stimulating hormone receptor in intracellular traffic and postendocytic processing. Front Cell Dev Biol. 2016;4:76.
   PubMedGoogle Scholar
• Munshi UM, Clouser CL, Peegel H, et al. Evidence that palmitoylation of carboxyl terminus cysteine residues of the human luteinizing hormone receptor regulates postendocytic processing. Mol Endocrinol. 2005;19:749–758.
   PubMedGoogle Scholar
• Arakawa T, Ejima D, Kita Y, et al. Small molecule pharmacological chaperones: from thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta. 2006;1764:1677–1687.
   PubMed Web of Science ®Google Scholar
• Bernier V, Lagace M, Bichet DG, et al. Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab. 2004;15:222–228.
   PubMed Web of Science ®Google Scholar
• Dandage R, Bandyopadhyay A, Jayaraj GG, et al. Classification of chemical chaperones based on their effect on protein folding landscapes. ACS Chem Biol. 2015;10:813–820.
   PubMed Web of Science ®Google Scholar
• Janovick JA, Patny A, Mosley R, et al. Molecular mechanism of action of pharmacoperone rescue of misrouted GPCR mutants: the GnRH receptor. Mol Endocrinol. 2009;23:157–168.
   PubMedGoogle Scholar
• Morello JP, Petaja-Repo UE, Bichet DG, et al. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci. 2000;21:466–469.
   PubMed Web of Science ®Google Scholar
• Loo TW, Clarke DM. Chemical and pharmacological chaperones as new therapeutic agents. Expert Rev Mol Med. 2007;9:1–18.
   PubMedGoogle Scholar
• Matouschek A, Pfanner N, Voos W. Protein unfolding by mitochondria. The Hsp70 import motor. EMBO Rep. 2000;1:404–410.
   PubMed Web of Science ®Google Scholar
• Ellis RJ, Minton AP. Protein aggregation in crowded environments. Biol Chem. 2006;387:485–497.
   PubMed Web of Science ®Google Scholar
• Smith JL, Reloj AR, Nataraj PS, et al. Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum. Am J Physiol Cell Physiol. 2013;305:C919C930.
   Web of Science ®Google Scholar
• Illing ME, Rajan RS, Bence NF, et al. A rhodopsin mutant linked to autosomal dominant retinitis pigmentosa is prone to aggregate and interacts with the ubiquitin proteasome system. J Biol Chem. 2002;277:34150–34160.
   PubMed Web of Science ®Google Scholar
• Huang H, Wang W, Tao YX. Pharmacological chaperones for the misfolded melanocortin-4 receptor associated with human obesity. Biochim Biophys Acta. 2017;1863:2496–2507.
   PubMed Web of Science ®Google Scholar
• Janovick JA, Goulet M, Bush E, et al. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J Pharmacol Exp Ther. 2003;305:608–614.
   PubMed Web of Science ®Google Scholar
• Los EL, Deen PM, Robben JH. Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus. J Neuroendocrinol. 2010;22:393–399.
   PubMed Web of Science ®Google Scholar
• Robben JH, Kortenoeven ML, Sze M, et al. Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. Proc Natl Acad Sci U S A. 2009;106:12195–12200.
   PubMed Web of Science ®Google Scholar
• Jean-Alphonse F, Perkovska S, Frantz MC, et al. Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J Am Soc Nephrol. 2009;20:2190–2203.
   PubMed Web of Science ®Google Scholar
• Ferreira CR, Gahl WA. Lysosomal storage diseases. Transl Sci Rare Dis. 2017;2:1–71.
   PubMedGoogle Scholar
• Porto C, Ferrara MC, Meli M, et al. Pharmacological enhancement of alpha-glucosidase by the allosteric chaperone N-acetylcysteine. Mol Ther. 2012;20:2201–2211.
   PubMed Web of Science ®Google Scholar
• Cavanaugh A, McKenna J, Stepanchick A, et al. Calcium-sensing receptor biosynthesis includes a cotranslational conformational checkpoint and endoplasmic reticulum retention. J Biol Chem. 2010;285:19854–19864.
   PubMed Web of Science ®Google Scholar
• Huang Y, Breitwieser GE. Rescue of calcium-sensing receptor mutants by allosteric modulators reveals a conformational checkpoint in receptor biogenesis. J Biol Chem. 2007;282:9517–9525.
   PubMed Web of Science ®Google Scholar
• White E, McKenna J, Cavanaugh A, et al. Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. Mol Endocrinol. 2009;23:1115–1123.
   PubMedGoogle Scholar
• Letz S, Rus R, Haag C, et al. Novel activating mutations of the calcium-sensing receptor: the calcilytic NPS-2143 mitigates excessive signal transduction of mutant receptors. J Clin Endocrinol Metab. 2010;95:E229E233.
   Web of Science ®Google Scholar
• Ulloa-Aguirre A, Zarinan T, Dias JA, et al. Mutations in G protein-coupled receptors that impact receptor trafficking and reproductive function. Mol Cell Endocrinol. 2014;382:411–423.
   PubMed Web of Science ®Google Scholar
• Newton CL, Whay AM, McArdle CA, et al. Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist. Proc Natl Acad Sci U S A. 2011;108:7172–7176.
   PubMed Web of Science ®Google Scholar
• Redler RL, Das J, Diaz JR, et al. Protein destabilization as a common factor in diverse inherited disorders. J Mol Evol. 2016;82:11–16.
   PubMed Web of Science ®Google Scholar
• Yang C, Asthagiri AR, Iyer RR, et al. Missense mutations in the NF2 gene result in the quantitative loss of merlin protein and minimally affect protein intrinsic function. Proc Natl Acad Sci U S A. 2011;108:4980–4985.
   PubMed Web of Science ®Google Scholar
• Kopito RR, Ron D. Conformational disease. Nat Cell Biol. 2000;2:E207–209.
   PubMed Web of Science ®Google Scholar
• Jaishy B, Abel ED. Lipids, lysosomes, and autophagy. J Lipid Res. 2016;57:1619–1635.
   PubMed Web of Science ®Google Scholar
• Klein AD, Futerman AH. Lysosomal storage disorders: old diseases, present and future challenges. Pediatr Endocrinol Rev. 2013;11(Suppl 1):59–63.
   PubMedGoogle Scholar
• Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103:641–659.
   PubMed Web of Science ®Google Scholar
• Valenzano KJ, Khanna R, Powe AC, et al. Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders. Assay Drug Dev Technol. 2011;9:213–235.
   PubMed Web of Science ®Google Scholar
• Staretz-Chacham O, Lang TC, LaMarca ME, et al. Lysosomal storage disorders in the newborn. Pediatrics. 2009;123:1191–1207.
   PubMed Web of Science ®Google Scholar
• Hsu TR, Niu DM. Fabry disease: review and experience during newborn screening. Trends Cardiovasc Med. 2018;28:274–281.
   PubMed Web of Science ®Google Scholar
• Ishii S. Pharmacological chaperone therapy for Fabry disease. Proc Jpn Acad Ser B Phys Biol Sci. 2012;88:18–30.
   PubMed Web of Science ®Google Scholar
• Sawkar AR, Cheng WC, Beutler E, et al. Chemical chaperones increase the cellular activity of N370S beta -glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci U S A. 2002;99:15428–15433.
   PubMed Web of Science ®Google Scholar
• Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci. 2017;18.
   Web of Science ®Google Scholar
• Brumshtein B, Greenblatt HM, Butters TD, et al. Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid beta-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease. J Biol Chem. 2007;282:29052–29058.
   PubMed Web of Science ®Google Scholar
• Compain P, Martin OR, Boucheron C, et al. Design and synthesis of highly potent and selective pharmacological chaperones for the treatment of Gaucher’s disease. Chembiochem. 2006;7:1356–1359.
   PubMed Web of Science ®Google Scholar
• Yu L, Ikeda K, Kato A, et al. Alpha-1-C-octyl-1-deoxynojirimycin as a pharmacological chaperone for Gaucher disease. Bioorg Med Chem. 2006;14:7736–7744.
   PubMed Web of Science ®Google Scholar
• Aflaki E, Borger DK, Moaven N, et al. A new glucocerebrosidase chaperone reduces alpha-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and Parkinsonism. J Neurosci. 2016;36:7441–7452.
   PubMed Web of Science ®Google Scholar
• Mazzulli JR, Zunke F, Isacson O, et al. alpha-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models. Proc Natl Acad Sci U S A. 2016;113:1931–1936.
   PubMed Web of Science ®Google Scholar
• Mazzulli JR, Zunke F, Tsunemi T, et al. Activation of beta-glucocerebrosidase reduces pathological alpha-synuclein and restores lysosomal function in Parkinson’s patient midbrain neurons. J Neurosci. 2016;36:7693–7706.
   PubMed Web of Science ®Google Scholar
• Baldo BA. Enzymes approved for human therapy: indications, mechanisms and adverse effects. BioDrugs. 2015;29:31–55.
   PubMed Web of Science ®Google Scholar
• Harmatz P. Enzyme replacement therapies and immunogenicity in lysosomal storage diseases: is there a pattern? Clin Ther. 2015;37:2130–2134.
   PubMed Web of Science ®Google Scholar
• Penati R, Fumagalli F, Calbi V, et al. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I. J Inherit Metab Dis. 2017;40:543–554.
   PubMed Web of Science ®Google Scholar
• Frustaci A, Chimenti C, Ricci R, et al. Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose-infusion therapy. N Engl J Med. 2001;345:25–32.
   PubMed Web of Science ®Google Scholar
• Fan JQ, Ishii S, Asano N, et al. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med. 1999;5:112–115.
   PubMed Web of Science ®Google Scholar
• Schneider HJ. Limitations and extensions of the lock-and-key principle: differences between gas state, solution and solid state structures. Int J Mol Sci. 2015;16:6694–6717.
   PubMed Web of Science ®Google Scholar
• Behere SP, Weindling SN. Inherited arrhythmias: the cardiac channelopathies. Ann Pediatr Cardiol. 2015;8:210–220.
   PubMed Web of Science ®Google Scholar
• Lieve KV, Wilde AA. Inherited ion channel diseases: a brief review. Europace. 2015;17(Suppl 2):ii1ii6.
   Google Scholar
• Abriel H, Zaklyazminskaya EV. Cardiac channelopathies: genetic and molecular mechanisms. Gene. 2013;517:1–11.
   PubMed Web of Science ®Google Scholar
• Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res. 2001;42:1007–1017.
   PubMed Web of Science ®Google Scholar
• O’Sullivan BP, Freedman SD. Cystic fibrosis. Lancet. 2009;373:1891–1904.
   PubMed Web of Science ®Google Scholar
• Ratjen FA. Cystic fibrosis: pathogenesis and future treatment strategies. Respir Care. 2009;54:595–605.
   PubMed Web of Science ®Google Scholar
• Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–1073.
   PubMed Web of Science ®Google Scholar
• Sheppard DN, Welsh MJ. Structure and function of the CFTR chloride channel. Physiol Rev. 1999;79:S23–45.
   PubMedGoogle Scholar
• Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics. 2009;3:281–290.
   PubMedGoogle Scholar
• Pettit RS, Fellner C. CFTR modulators for the treatment of cystic fibrosis. P T. 2014;39:500–511.
   PubMedGoogle Scholar
• Rowe SM, Verkman AS. Cystic fibrosis transmembrane regulator correctors and potentiators. Cold Spring Harb Perspect Med. 2013;3:a009761.
   PubMed Web of Science ®Google Scholar
• Cheung JC, Deber CM. Misfolding of the cystic fibrosis transmembrane conductance regulator and disease. Biochemistry. 2008;47:1465–1473.
   PubMed Web of Science ®Google Scholar
• Du K, Sharma M, Lukacs GL. The DeltaF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR. Nat Struct Mol Biol. 2005;12:17–25.
   PubMed Web of Science ®Google Scholar
• Jensen TJ, Loo MA, Pind S, et al. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell. 1995;83:129–135.
   PubMed Web of Science ®Google Scholar
• Meacham GC, Patterson C, Zhang W, et al. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat Cell Biol. 2001;3:100–105.
   PubMed Web of Science ®Google Scholar
• Ward CL, Omura S, Kopito RR. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell. 1995;83:121–127.
   PubMed Web of Science ®Google Scholar
• Sanguinetti MC, Jiang C, Curran ME, et al. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81:299–307.
   PubMed Web of Science ®Google Scholar
• Trudeau MC, Warmke JW, Ganetzky B, et al. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92–95.
   PubMed Web of Science ®Google Scholar
• Smith JL, Anderson CL, Burgess DE, et al. Molecular pathogenesis of long QT syndrome type 2. J Arrhythm. 2016;32:373–380.
   PubMedGoogle Scholar
• Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113:365–373.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Gong Q, Epstein ML, et al. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998;273:21061–21066.
   PubMed Web of Science ®Google Scholar
• Fukumoto D, Ding WG, Wada Y, et al. Novel intracellular transport-refractory mutations in KCNH2 identified in patients with symptomatic long QT syndrome. J Cardiol. 2018;71:401–408.
   PubMed Web of Science ®Google Scholar
• Thomas D, Kiehn J, Katus HA, et al. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res. 2003;60:235–241.
   PubMed Web of Science ®Google Scholar
• Furutani M, Trudeau MC, Hagiwara N, et al. Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation. 1999;99:2290–2294.
   PubMed Web of Science ®Google Scholar
• Hutt DM, Herman D, Rodrigues AP, et al. Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nat Chem Biol. 2010;6:25–33.
   PubMed Web of Science ®Google Scholar
• Hanrahan JW, Sampson HM, Thomas DY. Novel pharmacological strategies to treat cystic fibrosis. Trends Pharmacol Sci. 2013;34:119–125.
   PubMed Web of Science ®Google Scholar
• Birault V, Solari R, Hanrahan J, et al. Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis. Curr Opin Chem Biol. 2013;17:353–360.
   PubMed Web of Science ®Google Scholar
• Kim Chiaw P, Wellhauser L, Huan LJ, et al. A chemical corrector modifies the channel function of F508del-CFTR. Mol Pharmacol. 2010;78:411–418.
   PubMed Web of Science ®Google Scholar
• Kirby EF, Heard AS, Wang XR. Enhancing the potency of F508del correction: A multi-layer combinational approach to drug discovery for cystic fibrosis. J Pharmacol Clin Toxicol. 2013;1:1007.
   PubMedGoogle Scholar
• Sampson HM, Lam H, Chen PC, et al. Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines. Orphanet J Rare Dis. 2013;8:11.
   PubMed Web of Science ®Google Scholar
• Van Goor F, Hadida S, Grootenhuis PD, et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A. 2011;108:18843–18848.
   PubMed Web of Science ®Google Scholar
• Wang Y, Loo TW, Bartlett MC, et al. Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by binding to the protein. J Biol Chem. 2007;282:33247–33251.
   PubMed Web of Science ®Google Scholar
• Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol. 2016;8:127–140.
   PubMedGoogle Scholar
• Accurso FJ, Rowe SM, Clancy JP, et al. Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med. 2010;363:1991–2003.
   PubMed Web of Science ®Google Scholar
• Cholon DM, Quinney NL, Fulcher ML, et al. Potentiator ivacaftor abrogates pharmacological correction of DeltaF508 CFTR in cystic fibrosis. Sci Transl Med. 2014;6:246ra296.
   Web of Science ®Google Scholar
• Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–1672.
   PubMed Web of Science ®Google Scholar
• Lewis HA, Zhao X, Wang C, et al. Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure. J Biol Chem. 2005;280:1346–1353.
   PubMed Web of Science ®Google Scholar
• Kim Chiaw P, Eckford PD, Bear CE. Insights into the mechanisms underlying CFTR channel activity, the molecular basis for cystic fibrosis and strategies for therapy. Essays Biochem. 2011;50:233–248.
   PubMed Web of Science ®Google Scholar
• Yu W, Kim Chiaw P, Bear CE. Probing conformational rescue induced by a chemical corrector of F508del-cystic fibrosis transmembrane conductance regulator (CFTR) mutant. J Biol Chem. 2011;286:24714–24725.
   PubMed Web of Science ®Google Scholar
• Wang Y, Bartlett MC, Loo TW, et al. Specific rescue of cystic fibrosis transmembrane conductance regulator processing mutants using pharmacological chaperones. Mol Pharmacol. 2006;70:297–302.
   PubMed Web of Science ®Google Scholar
• Wellhauser L, Kim Chiaw P, Pasyk S, et al. A small-molecule modulator interacts directly with deltaPhe508-CFTR to modify its ATPase activity and conformational stability. Mol Pharmacol. 2009;75:1430–1438.
   PubMed Web of Science ®Google Scholar
• Ren HY, Grove DE, De La Rosa O, et al. VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1. Mol Biol Cell. 2013;24:3016–3024.
   PubMed Web of Science ®Google Scholar
• Gong Q, Jones MA, Zhou Z. Mechanisms of pharmacological rescue of trafficking-defective hERG mutant channels in human long QT syndrome. J Biol Chem. 2006;281:4069–4074.
   PubMed Web of Science ®Google Scholar
• Ficker E, Obejero-Paz CA, Zhao S, et al. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem. 2002;277:4989–4998.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Gong Q, January CT. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological Temperature Effects J Biol Chem. 1999;274:31123–31126.
   Google Scholar
• Ayon RJ, Fernandez RA, Yuan JX. Mutant hERG channel traffic jam. Focus on “Pharmacological Correction of Long QT-linked Mutations in KCNH2 (Herg) Increases the Trafficking of Kv11.1 Channels Stored in the Transitional Endoplasmic Reticulum”. Am J Physiol Cell Physiol. 2013;305:C916C918.
   Web of Science ®Google Scholar
• Delisle BP, Anderson CL, Balijepalli RC, et al. Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. J Biol Chem. 2003;278:35749–35754.
   PubMed Web of Science ®Google Scholar
• Kampinga HH, Craig EA. The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol. 2010;11:579–592.
   PubMed Web of Science ®Google Scholar
• Li K, Jiang Q, Bai X, et al. Tetrameric assembly of K(+) channels requires ER-located chaperone proteins. Mol Cell. 2017;65:52–65.
   PubMed Web of Science ®Google Scholar
• Ulloa-Aguirre A, Timossi C. Structure-function relationship of follicle-stimulating hormone and its receptor. Hum Reprod Update. 1998;4:260–283.
   PubMed Web of Science ®Google Scholar
• Ulloa-Aguirre A, Conn PM. Cellular endocrinology in health and disease. In: Ulloa-Aguirre A, Conn PM, Editor. Intracellular trafficking of G protein-coupled receptors to the plasma membrane in health and disease. Philadelphia, PA: Elsevier Inc.; 2014. p. 341–364.
   Google Scholar
• Bernier V, Bichet DG, Bouvier M. Pharmacological chaperone action on G-protein-coupled receptors. Curr Opin Pharmacol. 2004;4:528–533.
   PubMed Web of Science ®Google Scholar
• Conn PM, Janovick JA. Trafficking and quality control of the gonadotropin releasing hormone receptor in health and disease. Mol Cell Endocrinol. 2009;299:137–145.
   PubMed Web of Science ®Google Scholar
• Conn PM, Janovick JA, Brothers SP, et al. ‘Effective inefficiency’: cellular control of protein trafficking as a mechanism of post-translational regulation. J Endocrinol. 2006;190:13–16.
   PubMed Web of Science ®Google Scholar
• Garland SL. Are GPCRs still a source of new targets? J Biomol Screen. 2013;18:947–966.
   PubMed Web of Science ®Google Scholar
• Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there? Nat Rev Drug Discov. 2006;5:993–996.
   PubMed Web of Science ®Google Scholar
• Biebermann H, Schoneberg T, Krude H, et al. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol Metab. 1997;82:3471–3480.
   PubMed Web of Science ®Google Scholar
• Conn PM, Ulloa-Aguirre A, Ito J, et al. G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev. 2007;59:225–250.
   PubMed Web of Science ®Google Scholar
• D’Souza-Li L, Yang B, Canaff L, et al. Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia. J Clin Endocrinol Metab. 2002;87:1309–1318.
   PubMed Web of Science ®Google Scholar
• Fuchs S, Amiel J, Claudel S, et al. Functional characterization of three mutations of the endothelin B receptor gene in patients with Hirschsprung’s disease: evidence for selective loss of Gi coupling. Mol Med. 2001;7:115–124.
   PubMed Web of Science ®Google Scholar
• Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev. 2010;31:506–543.
   PubMed Web of Science ®Google Scholar
• Colley NJ, Cassill JA, Baker EK, et al. Defective intracellular transport is the molecular basis of rhodopsin-dependent dominant retinal degeneration. Proc Natl Acad Sci U S A. 1995;92:3070–3074.
   PubMed Web of Science ®Google Scholar
• Leanos-Miranda A, Ulloa-Aguirre A, Janovick JA, et al. In vitro coexpression and pharmacological rescue of mutant gonadotropin-releasing hormone receptors causing hypogonadotropic hypogonadism in humans expressing compound heterozygous alleles. J Clin Endocrinol Metab. 2005;90:3001–3008.
   PubMed Web of Science ®Google Scholar
• Tao YX. Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol Cell Endocrinol. 2005;239:1–14.
   PubMed Web of Science ®Google Scholar
• Tao YX. Inactivating mutations of G protein-coupled receptors and diseases: structure-function insights and therapeutic implications. Pharmacol Ther. 2006;111:949–973.
   PubMed Web of Science ®Google Scholar
• Kapoor H, Koolwal A, Singh A. Ivacaftor: a novel mutation modulating drug. J Clin Diagn Res. 2014;8:SE01–SE05.
   PubMedGoogle Scholar
• Casas-Gonzalez P, Scaglia HE, Perez-Solis MA, et al. Normal testicular function without detectable follicle-stimulating hormone. A novel mutation in the follicle-stimulating hormone receptor gene leading to apparent constitutive activity and impaired agonist-induced desensitization and internalization. Mol Cell Endocrinol. 2012;364:71–82.
   PubMed Web of Science ®Google Scholar
• Ulloa-Aguirre A, Timossi C. Biochemical and functional aspects of gonadotrophin-releasing hormone and gonadotrophins. Reprod Biomed Online. 2000;1:48–62.
   PubMedGoogle Scholar
• Ulloa-Aguirre A, Janovick JA, Leanos-Miranda A, et al. Misrouted cell surface GnRH receptors as a disease aetiology for congenital isolated hypogonadotrophic hypogonadism. Hum Reprod Update. 2004;10:177–192.
   PubMed Web of Science ®Google Scholar
• Maya-Nunez G, Janovick JA, Ulloa-Aguirre A, et al. Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site. J Clin Endocrinol Metab. 2002;87:2144–2149.
   PubMed Web of Science ®Google Scholar
• Brothers SP, Cornea A, Janovick JA, et al. Human loss-of-function gonadotropin-releasing hormone receptor mutants retain wild-type receptors in the endoplasmic reticulum: molecular basis of the dominant-negative effect. Mol Endocrinol. 2004;18:1787–1797.
   PubMedGoogle Scholar
• Janovick JA, Conn PM. Salt bridge integrates GPCR activation with protein trafficking. Proc Natl Acad Sci U S A. 2010;107:4454–4458.
   PubMed Web of Science ®Google Scholar
• Conn PM, Janovick JA. Drug development and the cellular quality control system. Trends Pharmacol Sci. 2009;30:228–233.
   PubMed Web of Science ®Google Scholar
• Morello JP, Bichet DG. Nephrogenic diabetes insipidus. Annu Rev Physiol. 2001;63:607–630.
   PubMed Web of Science ®Google Scholar
• Birnbaumer M. V2R structure and diabetes insipidus. Receptors Channels. 2002;8:51–56.
   PubMedGoogle Scholar
• Robben JH, Knoers NV, Deen PM. Cell biological aspects of the vasopressin type-2 receptor and aquaporin 2 water channel in nephrogenic diabetes insipidus. Am J Physiol Renal Physiol. 2006;291:F257F270.
   Web of Science ®Google Scholar
• Morello JP, Salahpour A, Laperriere A, et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest. 2000;105:887–895.
   PubMed Web of Science ®Google Scholar
• Albright JD, Reich MF, Delos Santos EG, et al. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem. 1998;41:2442–2444.
   PubMed Web of Science ®Google Scholar
• Robben JH, Sze M, Knoers NV, et al. Rescue of vasopressin V2 receptor mutants by chemical chaperones: specificity and mechanism. Mol Biol Cell. 2006;17:379–386.
   PubMed Web of Science ®Google Scholar
• Robben JH, Sze M, Knoers NV, et al. Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol. 2007;292:F253F260.
   Web of Science ®Google Scholar
• Moeller HB, Rittig S, Fenton RA. Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev. 2013;34:278–301.
   PubMed Web of Science ®Google Scholar
• Leanos-Miranda A, Janovick JA, Conn PM. Receptor-misrouting: an unexpectedly prevalent and rescuable etiology in gonadotropin-releasing hormone receptor-mediated hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2002;87:4825–4828.
   PubMed Web of Science ®Google Scholar
• Wuller S, Wiesner B, Loffler A, et al. Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem. 2004;279:47254–47263.
   PubMed Web of Science ®Google Scholar
• Nicholson JR, Kohler G, Schaerer F, et al. Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice. J Pharmacol Exp Ther. 2006;317:771–777.
   PubMed Web of Science ®Google Scholar
• Vos TJ, Caracoti A, Che JL, et al. Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem. 2004;47:1602–1604.
   PubMed Web of Science ®Google Scholar
• Fan ZC, Tao YX. Functional characterization and pharmacological rescue of melanocortin-4 receptor mutations identified from obese patients. J Cell Mol Med. 2009;13:3268–3282.
   PubMed Web of Science ®Google Scholar
• Chen M, Cai M, Aprahamian CJ, et al. Contribution of the conserved amino acids of the melanocortin-4 receptor in [corrected] [Nle4,D-Phe7]-alpha-melanocyte-stimulating [corrected] hormone binding and signaling. J Biol Chem. 2007;282:21712–21719.
   PubMed Web of Science ®Google Scholar
• Huang H, Tao YX. A small molecule agonist THIQ as a novel pharmacoperone for intracellularly retained melanocortin-4 receptor mutants. Int J Biol Sci. 2014;10:817–824.
   PubMed Web of Science ®Google Scholar
• Loeb LA, Loeb KR, Anderson JP. Multiple mutations and cancer. Proc Natl Acad Sci U S A. 2003;100:776–781.
   PubMed Web of Science ®Google Scholar
• Conn PM, Spicer TP, Scampavia L, et al. Assay strategies for identification of therapeutic leads that target protein trafficking. Trends Pharmacol Sci. 2015;36:498–505.
   PubMed Web of Science ®Google Scholar
• Bridges RJ, Bradbury NA. Cystic fibrosis, cistyc fibrosis transmembrane conductance regulator and drugs: insights from cellular trafficking. Handb Exp Pharmacol. 2018;245:385–425.
   PubMedGoogle Scholar