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Biased Agonist Pharmacochaperones: Small Molecules in the Toolbox for Selectively Modulating GPCR Activity

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Structure and Function of GPCRs

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 30))

Abstract

In recent years, biased agonists as well as pharmacological chaperones have demonstrated the potential to harness G protein-coupled receptor signaling and trafficking and have collectively opened new possibilities in G protein-coupled receptor drug discovery. Combining pharmacological chaperoning and biased agonism properties into a unique given molecule would be of high therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. This strategy perfectly applies to congenital nephrogenic diabetes insipidus which is a typical conformational disease. In most of the cases, it is associated with inactivating mutations of the renal arginine vasopressin V2 receptor leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of specific ligands such as antagonists, agonists, as well as biased agonists of the V2 receptor have proven their usefulness as efficient pharmacological chaperones. These compounds, and particularly small-molecule-biased agonists which only trigger the V2-induced Gs protein-dependent signaling pathway, represent a potential therapeutic treatment of this X-linked genetic pathology.

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Abbreviations

3D:

Three-dimensional

AQP2:

Aquaporin-2

AVP:

Arginine vasopressin

cAMP:

Cyclic adenosine monophosphate

cNDI:

Congenital nephrogenic diabetes insipidus

ER:

Endoplasmic reticulum

FDA:

US food and drug administration

GnRHR:

Gonadotropin-releasing hormone receptor

GPCR:

G protein-coupled receptor

Gs:

G protein subunit αs

LSD:

Lysosomal storage disorder

NMR:

Nuclear magnetic resonance

OT:

Oxytocin

PC:

Pharmacological chaperone, pharmacochaperone, pharmacoperone

PCT:

Pharmacological chaperone therapy

TM:

Transmembrane

V2R:

Vasopressin type 2 receptor

References

  1. Galandrin S, Oligny-Longpré G, Bouvier M (2007) The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol Sci 28(8):423–430

    Article  CAS  PubMed  Google Scholar 

  2. Lutrell LM (2014) More than just a hammer: ligand “bias” and pharmaceutical discovery. Mol Endocrinol 28(3):281–294

    Article  CAS  Google Scholar 

  3. Luttrell LM, Maudsley S, Bohn LM (2015) Fulfilling the promise of “biased” G protein-coupled receptor agonism. Mol Pharmacol 88(3):579–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reiter E, Ahn S, Shukla AK, et al (2012) Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors. Annu Rev Pharmacol Toxicol 52:179–197

    Article  CAS  PubMed  Google Scholar 

  5. Laugwitz KL, Allgeier A, Offermanns S, et al (1996) The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc Natl Acad Sci U S A 93(1):116–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Offermanns S, Wieland T, Homann D, et al (1994) Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11. Mol Pharmacol 45(5):890–898

    CAS  PubMed  Google Scholar 

  7. Holloway AC, Qian H, Pipolo L, et al (2002) Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1A angiotensin receptors. Mol Pharmacol 61(4):768–777

    Article  CAS  PubMed  Google Scholar 

  8. Sagan S, Chassaing G, Pradier L, et al (1996) Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors. J Pharmacol Exp Ther 276(3):1039–1048

    CAS  PubMed  Google Scholar 

  9. Takasu H, Gardella TJ, Luck MD, et al (1999) Amino-terminal modifications of human parathyroid hormone (PTH) selectively alter phospholipase C signaling via the type 1 PTH receptor: implications for design of signal-specific PTH ligands. Biochemistry 38(41):13453–13460

    Article  CAS  PubMed  Google Scholar 

  10. Ferguson SS (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev 53(1):1–24

    CAS  PubMed  Google Scholar 

  11. Rajagopal S, Rajagopal K, Lefkowitz RJ (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov 9(5):373–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shenoy S, Lefkowitz RJ (2011) β-arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci 32(9):521–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Luttrell LM, Gesty-Palmer D (2010) Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 62(2):305–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carter AA, Hill SJ (2005) Characterization of isoprenaline- and salmeterol-stimulated interactions between beta2-adrenoceptors and beta-arrestin 2 using beta-galactosidase complementation in C2C12 cells. J Pharmacol Exp Ther 315(2):839–848

    Article  CAS  PubMed  Google Scholar 

  15. Wisler JW, DeWire SM, Whalen EJ, et al (2007) A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A 104(42):16657–16662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen X, Sassano MF, Zheng L, et al (2012) Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D2 receptor agonists. J Med Chem 55(16):7141–7153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thurmond RL, Desai PJ, Dunford PJ, et al (2004) A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 309(1):404–413

    Article  CAS  PubMed  Google Scholar 

  18. Semple G, Skinner PJ, Gharbaoui T, et al (2008) 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (MK-0354): a partial agonist of the nicotinic acid receptor, G-protein coupled receptor 109a, with antilipolytic but no vasodilatory activity in mice. J Med Chem 51(16):5101–5108

    Article  CAS  PubMed  Google Scholar 

  19. Groer CE, Tidgewell K, Moyer RA, et al (2007) An opioid agonist that does not induce mu-opioid receptor-arrestin interactions or receptor internalization. Mol Pharmacol 71(2):549–557

    Article  CAS  PubMed  Google Scholar 

  20. Violin JD, DeWire SM, Yamashita D, et al (2010) Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther 335(3):572–579

    Article  CAS  PubMed  Google Scholar 

  21. Chaudhuri TK, Paul S (2006) Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J 273(7):1331–1349

    Article  CAS  PubMed  Google Scholar 

  22. Cohen FE, Kelly LW (2003) Therapeutic approaches to protein-misfolding diseases. Nature 426(6968):905–909

    Article  CAS  PubMed  Google Scholar 

  23. Sato S, Ward CL, Krouse ME, et al (1996) Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 271(2):635–638

    Article  CAS  PubMed  Google Scholar 

  24. Loo TW, Clarke DM (1997) Correction of defective protein kinesis of human P-glycoprotein mutants by substrates and modulators. J Biol Chem 272(2):709–712

    Article  CAS  PubMed  Google Scholar 

  25. Morello JP, Salahpour A, Laperrière A, et al (2000) Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105(7):887–895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morello JP, Petäjä-Repo UE, Bichet DG, et al (2000) Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21(12):466–469

    Article  CAS  PubMed  Google Scholar 

  27. Bernier V, Bichet DG, Bouvier M (2004) Pharmacological chaperone action on G protein-coupled receptors. Curr Opin Pharmacol 4(5):528–533

    Article  CAS  PubMed  Google Scholar 

  28. Bernier V, Morello JP, Zarruk A, et al (2006) Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am Soc Nephrol 17(1):233–243

    Article  CAS  Google Scholar 

  29. Conn PM, Ulloa-Aguirre A (2010) Trafficking of G protein-coupled receptors to the plasma membrane: insights from pharmacoperone drugs. Trends Endocrinol Metab 21(3):190–197

    Article  CAS  PubMed  Google Scholar 

  30. Conn PM, Smithson DC, Hodder PS, et al (2014) Transitioning pharmacoperones to therapeutic use: in vivo proof-of-principle and design of high throughput screens. Pharmacol Res 83:38–51

    Article  CAS  PubMed  Google Scholar 

  31. Leidenheimer NJ, Ryder KG (2014) Pharmacological chaperoning: a primer on mechanism and pharmacology. Pharmacol Res 83:10–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Karageorgos LE, Isaac EL, Brooks DA, et al (1997) Lysosomal biogenesis in lysosomal storage disorders. Exp Cell Res 234(1):85–97

    Article  CAS  PubMed  Google Scholar 

  33. Parkinson-Lawrence EJ, Shandala T, Prodoehl M, et al (2010) Lysosomal storage disease: revealing lysosomal function and physiology. Physiology (Bethesda) 25(2):102–115

    CAS  Google Scholar 

  34. Parenti G, Andria G, Valenzano KJ (2015) Pharmacological chaperone therapy: preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders. Mol Ther 23(7):1138–1148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brady RO (2006) Enzyme replacement for lysosomal diseases. Annu Rev Med 57:283–296

    Article  CAS  PubMed  Google Scholar 

  36. Platt FM, Jeyakumar M (2008) Substrate reduction therapy. Acta Paediatr 97(457):88–93

    Article  PubMed  Google Scholar 

  37. Germain DP, Giugliani R, Hughes DA, et al (2012) Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. Orphanet J Rare Dis 7:91

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zimran A, Altarescu G, Elstein D (2013) Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis 50(2):134–137

    Article  CAS  PubMed  Google Scholar 

  39. Germain DP, Hughes DA, Nicholls K, et al (2016) Treatment of Fabry’s disease with the pharmacologic chaperone Migalastat. N Engl J Med 375(6):545–555

    Article  CAS  PubMed  Google Scholar 

  40. Conn PM, Ulloa-Aguirre A (2011) Pharmacological chaperones for misfolded gonadotropin-releasing hormone receptors. Adv Pharmacol 62:109–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Conn PM, Ulloa-Aguire A, Ito J, et al (2007) G protein-coupled receptor trafficking in health and disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev 59(3):225–250

    Article  CAS  PubMed  Google Scholar 

  42. 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(7):3255–3262

    Article  CAS  PubMed  Google Scholar 

  43. Janovick JA, Stewart MD, Jacob D, et al (2013) Restoration of testis function in hypogonadotropic hypogonadal mice harboring a misfolded GnRHR mutant by pharmacoperone drug therapy. Proc Natl Acad Sci U S A 110(52):21030–21035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jean-Alphonse F, Perkovska S, Frantz MC, et al (2009) Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J Am Soc Nephrol 20(10):2190–2203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. White E, McKenna J, Cavanaugh A, et al (2009) Pharmacochaperone-mediated rescue of calcium-sensing receptor loss-of-function mutants. Mol Endocrinol 23(7):1115–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Janovick JA, Maya-Nunez G, Ullo-Aguire A, et al (2009) Increased plasma membrane expression of human follicle-stimulating hormone receptor by a small molecule thienopyr(im)idine. Mol Cell Endocrinol 298(1–2):84–88

    Article  CAS  PubMed  Google Scholar 

  47. Newton CL, Whay AM, McArdle CA, et al (2011) 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 108(17):7172–7176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Aronson D, Verbalis JG, Mueller M, et al (2011) Short- and long-term treatment of dilutional hyponatraemia with satavaptan, a selective arginine-vasopressin V2 receptor antagonist: the DILIPO study. Eur J Heart Fail 13(3):327–336

    Article  CAS  PubMed  Google Scholar 

  49. Feinstein TN, Yui N, Webber MJ, et al (2013) Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J Biol Chem 288(39):27849–27860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Moeller HB, Rittig S, Fenton RA (2013) Nephrogenic diabetes insipidus: essential insights into the molecular background and potential therapies for treatment. Endocr Rev 34(2):278–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Treschan TA, Peters J (2006) The vasopressin system. Anesthesiology 105(3):599–612

    Article  CAS  PubMed  Google Scholar 

  52. Morello JP, Bichet DG (2001) Nephrogenic diabetes insipidus. Annu Rev Physiol 63:607–630

    Article  CAS  PubMed  Google Scholar 

  53. Bichet DG, Birnbaumer M, Lonergan M, et al (1994) Nature and recurrence of AVPR2 mutations in X-linked nephrogenic diabetes insipidus. Am J Hum Genet 55(2):278–286

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Tsukagushi H, Matsubara H, Taketani S, et al (1995) Binding, intracellular transport and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus. J Clin Invest 96(4):2043–2050

    Article  Google Scholar 

  55. Ala Y, Morin D, Mouillac B, et al (1998) Functional studies of twelve mutant V2 vasopressin receptors related to nephrogenic diabetes insipidus: molecular basis of a mild clinical phenotype. J Am Soc Nephrol 9(10):1861–1872

    CAS  PubMed  Google Scholar 

  56. Bockenhauer D, Bichet DG (2014) Urinary concentration: different ways to open and close the tap. Pediatr Nephrol 29(8):1297–1303

    Article  PubMed  Google Scholar 

  57. Birnbaumer M, Seibold A, Gilbert S, et al (1992) Molecular cloning of the receptor for human antidiuretic hormone. Nature 357(6376):333–335

    Article  CAS  PubMed  Google Scholar 

  58. Lolait SJ, Carroll AM, McBride OW, et al (1992) Cloning and characterization of a vasopressin V2 receptor and possible link to nephrogenic diabetes insipidus. Nature 357(6376):526–529

    Article  Google Scholar 

  59. Rosenthal W, Seibold A, Antaramian A, et al (1992) Molecular identification of the gene responsible for congenital nephrogenic diabetes insipidus. Nature 359(6392):233–235

    Article  CAS  PubMed  Google Scholar 

  60. Tamarappoo BK, Verkman AS (1998) Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 101(10):2257–2267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Serradeil-Le Gal C, Lacour C, Valette G, et al (1996) Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. J Clin Invest 98(12):2729–2738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bockenhauer D, Carpentier E, Rochdi D, et al (2010) Vasopressin type 2 receptor V88M mutation: molecular basis of partial and complete nephrogenic diabetes insipidus. Nephron Physiol 114(1):1–10

    Article  CAS  Google Scholar 

  63. Janovick JA, Park BS, Conn PM (2011) Therapeutic rescue of misfolded mutants: validation of primary high throughput screens for identification of pharmacoperone drugs. PLoS One 6(7):e22784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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(37):35678–35686

    Article  CAS  PubMed  Google Scholar 

  65. Wüller S, Wiesner B, Loffler A, et al (2004) Pharmacochaperones post-translationally enhance cell surface expression by increasing conformational stability of wild-type and mutant vasopressin V2 receptors. J Biol Chem 279(45):47254–47263

    Article  PubMed  CAS  Google Scholar 

  66. Bernier V, Lagacé M, Lonergan M, et al (2004) Functional rescue of the constitutively internalized V2 vasopressin receptor mutant R137H by the pharmacological chaperone action of SR49059. Mol Endocrinol 18(8):2074–2084

    Article  CAS  PubMed  Google Scholar 

  67. Robben JH, Sze M, Knoers NV, et al (2007) Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol 292(1):F253–F260

    Article  CAS  PubMed  Google Scholar 

  68. Robben JH, Sze M, Knoers NV, et al (2006) Rescue of vasopressin V2 receptor mutants by chemical chaperones: specificity and mechanism. Mol Biol Cell 17(1):379–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Robben JH, Kortenoeven MLA, Sze M, et al (2009) Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. Proc Natl Acad Sci U S A 106(29):12195–12200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Auzan RJ, Ventura MA, Clauser E (2005) Mechanisms of cell-surface rerouting of an endoplasmic reticulum-retained mutant of the vasopressin V1b/V3 receptor by a pharmacological chaperone. J Biol Chem 280(51):42198–42206

    Article  PubMed  Google Scholar 

  71. Hawtin SR (2006) Pharmacological chaperone activity of SR49059 to functionally recover misfolded mutations of the vasopressin V1a receptor. J Biol Chem 281(21):14604–14614

    Article  CAS  PubMed  Google Scholar 

  72. Mendre C, Mouillac B (2010) Pharmacological chaperones: a potential therapeutic treatment for conformational diseases. Med Sci (Paris) 26(6–7):627–635

    Article  Google Scholar 

  73. Los EL, Deen PMT, Robben JH (2010) Potential of nonpeptide (ant)agonists to rescue vasopressin V2 receptor mutants for the treatment of X-linked nephrogenic diabetes insipidus. J Neuroendocrinol 22(5):393–399

    Article  CAS  PubMed  Google Scholar 

  74. Wesche D, Deen PMT, Knoers NV (2012) Congenital nephrogenic diabetes insipidus: the current state of affairs. Pediatr Nephrol 27(12):2183–2204

    Article  PubMed  Google Scholar 

  75. Schrier RW, Gross P, Gheorghiade M (2006) Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355(20):2099–2112

    Article  CAS  PubMed  Google Scholar 

  76. Mouillac B, Mendre C (2014) Vasopressin receptors and pharmacological chaperones: from functional rescue to promising therapeutic strategies. Pharmacol Res 83:74–78

    Article  CAS  PubMed  Google Scholar 

  77. Rahmeh R, Damian M, Cottet M, et al (2012) Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc Natl Acad Sci U S A 109(17):6733–6738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mary S, Damian M, Louet M, et al (2012) Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor. Proc Natl Acad Sci U S A 109(21):8304–8309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Liu JJ, Horst R, Katritch V, et al (2012) Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science 335(6072):1106–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Institut de Génomique Fonctionnelle, CNRS, INSERM, Université de Montpellier, 34094, Montpellier, France

    Bernard Mouillac & Christiane Mendre

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  1. Bernard Mouillac
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  2. Christiane Mendre
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Correspondence to Bernard Mouillac .

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  1. Institut de Génomique Fonctionnelle Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Montpellier, Montpellier, France

    Guillaume Lebon

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Mouillac, B., Mendre, C. (2017). Biased Agonist Pharmacochaperones: Small Molecules in the Toolbox for Selectively Modulating GPCR Activity. In: Lebon, G. (eds) Structure and Function of GPCRs. Topics in Medicinal Chemistry, vol 30. Springer, Cham. https://doi.org/10.1007/7355_2017_14

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