Advertisement

Towards the Rational Design of Hormone Analogs Which Complement Receptor Mutations

  • John T. Koh
  • Marc C. Putnam
Chapter
  • 134 Downloads
Part of the Endocrine Updates book series (ENDO, volume 22)

Abstract

Mutations to nuclear and steroid hormone receptors (NHRs) are associated with a variety of human genetic diseases (1–3). These mutations generally result in reduced ligand binding or impaired ligand-dependent transactivation (or trans-repression) response. Individuals having mutant receptors that show reduced hormone responsiveness can often be treated with high doses of the natural hormone, however, often supraphysiological doses of hormone can create undesirable side effects that can be ascribed to inappropriate activation of other receptor subtypes and/or other samehormone responsive receptors (4, 5). In such cases hormone analogs have been empirically been used which may be able to impart greater potency activity and selectivity with mutant receptors. Thus far the use of hormone analogs for the functional rescue of impaired receptors has been largely empirical. The high-resolution structures of nuclear receptors may provide the basis to use rational molecular design strategies to efficiently create custom-designed hormone analogs, which may be able to bind to mutant receptors with greater activity, potency and selectivity than the natural hormone or existing hormone analogs. Currently relatively few examples of molecular complementation are known. This chapter will discuss examples from related nuclear receptors and other non-NHR examples to provide perspective to this exciting new area of research.

Keywords

Thyroid Hormone Thyroid Hormone Receptor Hormone Analog Natural Hormone Androgen Insensitivity Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Burris TP, McCabe ERB (eds) 2001 Nuclear Receptors and Genetic Disease. Academic Press, San DiegoGoogle Scholar
  2. 2.
    Tenbaum S, Baniahmad A 1997 Nuclear receptors: structure, function and involvement in disease. Int J Biochem Cell Biol 29:1325–41PubMedCrossRefGoogle Scholar
  3. 3.
    Latchman DS 1996 Transcription-factor mutations and disease. N Engl J Med 334:28–33PubMedCrossRefGoogle Scholar
  4. 4.
    Takeda T, Suzuki S, Liu RT, DeGroot LJ 1995 Triiodothyroacetic acid has unique potential for therapy of resistance to thyroid hormone. J Clin Endocrinol Metab 80:2033–40PubMedCrossRefGoogle Scholar
  5. 5.
    Weiss RE, Refetoff S 1999 Treatment of resistance to thyroid hormone — Primum non nocere. Journal of Clinical Endocrinology and Metabolism 84:401–404PubMedCrossRefGoogle Scholar
  6. 6.
    Barroso I, Gurnell M, Crowley VE, et al. 1999 Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension [see comments]. Nature 402:880–3PubMedGoogle Scholar
  7. 7.
    Steinmetz ACU, Renaud JP, Moras D 2001 Binding of ligands and activation of transcription by nuclear receptors. Annual Review of Biophysics and Biomolecular Structure 30:329–359PubMedCrossRefGoogle Scholar
  8. 8.
    Aranda A, Pascual A 2001 Nuclear hormone receptors and gene expression. Physiol Rev 81:1269–304.PubMedGoogle Scholar
  9. 9.
    Weatherman RV, Fletterick RJ, Scanlan TS 1999 Nuclear-receptor ligands and ligand-binding domains. Annu Rev Biochem 68:559–81PubMedCrossRefGoogle Scholar
  10. 10.
    Meier CA, Parkison C, Chen A, et al. 1993 Interaction of Human Beta-1 ThyroidHormone Receptor and Its Mutants with DNA and Retinoid-X Receptor-Beta T(3) Response Element Dependent Dominant-Negative Potency. Journal of Clinical Investigation 92:1986–1993PubMedCrossRefGoogle Scholar
  11. 11.
    Collingwood TN, Wagner R, Matthews CH, et al. 1998 A role for helix 3 of the TRbeta ligand-binding domain in coactivator recruitment identified by characterization of a third cluster of mutations in resistance to thyroid hormone. Embo J 17:4760–70PubMedCrossRefGoogle Scholar
  12. 12.
    Liu Y, Takeshita A, Misiti S, Chin WW, Yen PM 1998 Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors. Endocrinology 139:4197–204PubMedCrossRefGoogle Scholar
  13. 13.
    Yoh SM, Privalsky ML 2000 Resistance to thyroid hormone (RTH) syndrome reveals novel determinants regulating interaction of T3 receptor with corepressor [published erratum appears in Mol Cell Endocrinol 2000 Apr 25;162(1–2):235]. Mol Cell Endocrinol 159:109–24Google Scholar
  14. 14.
    Clifton-Bligh RJ, de Zegher F, Wagner RL, et al. 1998 A novel TR beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative transcriptional regulation. Mol Endocrinol 12:609–21PubMedCrossRefGoogle Scholar
  15. 15.
    Piedrafita FJ, Ortiz MA, Pfahl M 1995 Thyroid hormone receptor-beta mutants associated with generalized resistance to thyroid hormone show defects in their ligand-sensitive repression function. Mol Endocrinol 9:1533–48PubMedCrossRefGoogle Scholar
  16. 16.
    Malloy PJ, Feldman D 1999 Vitamin D resistance. Am J Med 106:355–70PubMedCrossRefGoogle Scholar
  17. 17.
    Groenhout EG, Dorin RI 1994 Generalized thyroid hormone resistance due to a deletion of the carboxy terminus of the c-erbA beta receptor. Mol Cell Endocrinol 99:81–8PubMedCrossRefGoogle Scholar
  18. 18.
    Phillips SA, Rotman-Pikielny P, Lazar J, et al. 2001 Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant. Journal of Clinical Endocrinology and Metabolism 86:5142–5147PubMedCrossRefGoogle Scholar
  19. 19.
    Bernier V, Morello JP, Salahpour A, et al. 2002 A pharmacological chaperone acting at the V2-vasopressin receptor offers a treatment for nephrogenic diabetes insipidus. Faseb Journal 16:A142-A143Google Scholar
  20. 20.
    Morello JP, Salahpour A, Laperriere A, et al. 2000 Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. Journal of Clinical Investigation 105:887–895PubMedCrossRefGoogle Scholar
  21. 21.
    Foster BA, Coffey HA, Morin MJ, Rastinejad F 1999 Pharmacological rescue of mutant p53 conformation and function [see comments]. Science 286:2507–10PubMedCrossRefGoogle Scholar
  22. 22.
    Ames BN, Elson-Schwab I, Silver EA 2002 High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K-m): relevance to genetic disease and polymorphisms. American Journal of Clinical Nutrition 75:616–658PubMedGoogle Scholar
  23. 23.
    Gardezi SA, Nguyen C, Malloy PJ, Posner GH, Feldman D, Peleg S 2001 A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,25-dihydroxyvitamin D-3. Journal of Biological Chemistry 276:29148–29156PubMedCrossRefGoogle Scholar
  24. 24.
    Bishop AC, Ubersax JA, Petsch DT, et al. 2000 A chemical switch for inhibitorsensitive alleles of any protein kinase. Nature 407:395–401PubMedCrossRefGoogle Scholar
  25. 25.
    Belshaw PJ, Schoepfer JG, Liu K-Q, Morrison KL, Schreiber SL 1995 Rational Design of Orthogonal Receptor-Ligand Combinations. Angew. Chem., Int. Ed. Engl. 34:2129–2132CrossRefGoogle Scholar
  26. 26.
    Liu Y, Shah K, Yang F, Witucki L, Shokat KM 1998 Engineering Src family protein kinases with unnatural nucleotide specificity. Chem. Biol. 5:91–101.PubMedCrossRefGoogle Scholar
  27. 27.
    Lin Q, Jiang FY, Schultz PG, Gray NS 2001 Design of allele-specific protein methyltransferase inhibitors. Journal of the American Chemical Society 123:11608–11613PubMedCrossRefGoogle Scholar
  28. 28.
    Witucki LA, Huang X, Shah K, et al. 2002 Mutant tyrosine kinases with unnatural nucleotide specificity retain the structure and phospho-acceptor specificity of the wild-type enzyme. Chemistry & Biology 9:25–33CrossRefGoogle Scholar
  29. 29.
    Gillespie PG, Gillespie SK, Mercer JA, Shah K, Shokat KM 1999 Engineering of the myosin-ibeta nucleotide-binding pocket to create selective sensitivity to N(6)-modified ADP analogs. J. Biol. Chem. 274:31373–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Tedesco R, Thomas JA, Katzenellenbogen BS, Katzenellenbogen JA 2001 The estrogen receptor: a structure-based approach to the design of new specific hormone-receptor combinations. Chem. Biol. 8:277–87.PubMedCrossRefGoogle Scholar
  31. 31.
    Shi YH, Koh JT 2002 Functionally orthogonal ligand-receptor pairs for the selective regulation of gene expression generated by manipulation of charged residues at the ligand-receptor interface of ER alpha and ER beta. Journal of the American Chemical Society 124:6921–6928PubMedCrossRefGoogle Scholar
  32. 32.
    Shi Y, Koh JT 2001 Selective regulation of gene expression by an orthogonal estrogen receptor-ligand pair created by polar-group exchange. Chem. Biol. 8:501–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Doyle DF, Mangelsdorf DJ, Corey DR 2000 Modifying ligand specificity of gene regulatory proteins. Curr Opin Chem Biol 4:60–3PubMedCrossRefGoogle Scholar
  34. 34.
    Doyle DF, Braasch DA, Jackson LK, et al. 2001 Engineering Orthogonal LigandReceptor Pairs From “Near Drugs”. J. Am. Chem. Soc. 123:11367–11371PubMedCrossRefGoogle Scholar
  35. 35.
    Peet DJ, Doyle DF, Corey DR, Mangelsdorf DJ 1998 Engineering novel specificities for ligand-activated transcription in the nuclear hormone receptor RXR. Chem. Biol. 5:13–21PubMedCrossRefGoogle Scholar
  36. 36.
    Miller N, Whelan J 1998 Random mutagenesis of human estrogen receptor ligand binding domain identifies mutations that decrease sensitivity to estradiol and increase sensitivity to a diphenol indene-ol compound: basis for a regulatable expression system. J. Steroid. Biochem. Mol. Biol. 64:129–35PubMedCrossRefGoogle Scholar
  37. 37.
    Refetoff S, Weiss RE, Usala SJ 1993 The syndromes of resistance to thyroid hormone. Endocr Rev 14:348–99PubMedGoogle Scholar
  38. 38.
    Messier N, Langlois MF 2000 Triac regulation of transcription is T-3 receptor isoform- and response element-specific. Molecular and Cellular Endocrinology 165:57–66PubMedCrossRefGoogle Scholar
  39. 39.
    Farach-Carson MC, Ridall AL 1998 Dual 1,25-dihydroxyvitamin D3 signal response pathways in osteoblasts: cross-talk between genomic and membraneinitiated pathways. Am J Kidney Dis 31:729–42PubMedCrossRefGoogle Scholar
  40. 40.
    Khoury R, Ridall AL, Norman AW, Farachcarson MC 1993 Analogs of VitaminD(3) Selectively Activate Genomic and Nongenomic Pathways in Osteoblasts. Journal of Bone and Mineral Research 8:S220-S220Google Scholar
  41. 41.
    Malloy PJ, Pike JW, Feldman D 1999 The vitamin D receptor and the syndrome of hereditary 1,25- dihydroxyvitamin D-resistant rickets. Endocr Rev 20:156–88PubMedCrossRefGoogle Scholar
  42. 42.
    Malloy PJ, Eccleshall TR, Gross C, VanMaldergem L, Bouillon R, Feldman D 1997 Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. Journal of Clinical Investigation 99:297–304PubMedCrossRefGoogle Scholar
  43. 43.
    Kristjansson K, Rut AR, Hewison M, O’Riordan JL, Hughes MR 1993 Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3. J Clin Invest 92:12–6PubMedCrossRefGoogle Scholar
  44. 44.
    Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D 2000 The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell 5:173–9PubMedCrossRefGoogle Scholar
  45. 45.
    Swann SL, Bergh J, Mary C. Farach-Carson, Ocasio CA, Koh JT 2002 Structure based design of selective agonists for a rickets-associated mutant of the vitamin D receptor. J. Am. Chem. Soc. in press Google Scholar
  46. 46.
    Swann SL, Bergh JJ, Farach-Carson MC, Koh JT 2002 Rational Design of Vitamin D3 Analogs Which Selectively Restore Activity to a Vitamin D Receptor Mutant Associated With Rickets. Org. Lett. in press Google Scholar
  47. 47.
    Wagner R, Apriletti JW, McGarth ME, West BL, Baxter JD, Fletterick RJ 1995 A structural role for hormone in the thyroid hormone receptor. Nature 378:690–697PubMedCrossRefGoogle Scholar
  48. 48.
    Yen PM 2001 Physiological and molecular basis of thyroid hormone action. Physiological Reviews 81:1097–1142PubMedGoogle Scholar
  49. 49.
    Beckpeccoz P, Chatterjee VKK 1994 The Variable Clinical Phenotype in ThyroidHormone Resistance Syndrome. Thyroid 4:225–232CrossRefGoogle Scholar
  50. 50.
    Kahaly GJ, Matthews CH, Mohr-Kahaly S, Richards CA, Chatterjee VKK 2002 Cardiac involvement in thyroid hormone resistance. Journal of Clinical Endocrinology and Metabolism 87:204–212PubMedCrossRefGoogle Scholar
  51. 51.
    Wikstrom L, Johansson C, Salto C, et al. 1998 Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. Embo Journal 17:455–461PubMedCrossRefGoogle Scholar
  52. 52.
    Scanlan TS, Yoshihara HA, Nguyer N, Chiellini G 2001 Selective Thyromimetics: Tissue-selective thyroid hormone analogs. Current Opinion in Drug Discovery and Development 4:614–622Google Scholar
  53. 53.
    Messier N, Laflamme L, Hamann G, Langlois MF 2001 In vitro effect of Triac on resistance to thyroid hormone receptor mutants: potential basis for therapy. Molecular and Cellular Endocrinology 174:59–69PubMedCrossRefGoogle Scholar
  54. 54.
    Smallridge RC, Parker RA, Wiggs EA, Rajagopal KR, Fein HG 1989 Thyroid hormone resistance in a large kindred: physiologic, biochemical, pharmacologic, and neuropsychologic studies [published erratum appears in Am J Med 1989 May;86(5):637]. Am J Med 86:289–96Google Scholar
  55. 55.
    Ueda S, Takamatsu J, Fukata S, et al. 1996 Differences in response of thyrotropin to 3,5,3′-triiodothyronine and 3,5,3′-triiodothyroacetic acid in patients with resistance to thyroid hormone. Thyroid 6:563–70PubMedCrossRefGoogle Scholar
  56. 56.
    Darendeliler F, Bas F 1997 Successful therapy with 3,5,3′-triiodothyroacetic acid (TRIAC) in pituitary resistance to thyroid hormone. J Pediatr Endocrinol Metab 10:535–8PubMedCrossRefGoogle Scholar
  57. 57.
    Beck-Peccoz P, Piscitelli G, Cattaneo MG, Fagiia G 1983 Effectiveness of 3,5,3′ Triiodothyroacetic Acid (Triac), but Not Bromocriptine, in Lowering Tsh Secretion in One Hyperthyroid Patient with Non-Neoplastic Pituitary Tsh Hypersecretion. Annales D Endocrinologie 44:A38-A38Google Scholar
  58. 58.
    Schueler PA, Schwartz HL, Strait KA, Mariash CN, Oppenheimer JH 1990 Binding of 3,5,3′-Triiodothyronine (T3) and Its Analogs to the Invitro Translational Products of C-Erba Protooncogenes — Differences in the Affinity of the Alpha-Forms and Beta-Forms for the Acetic-Acid Analog and Failure of the Human Testis and Kidney Alpha-2 Products to Bind T3. Molecular Endocrinology 4:227–234PubMedCrossRefGoogle Scholar
  59. 59.
    Wagner RL, Huber BR, Shiau AK, et al. 2001 Hormone selectivity in thyroid hormone receptors. Molecular Endocrinology 15:398–410PubMedCrossRefGoogle Scholar
  60. 60.
    Chiellini G, Apriletti JW, al Yoshihara H, Baxter JD, Ribeiro RC, Scanlan TS 1998 A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. Chem Biol 5:299–306PubMedCrossRefGoogle Scholar
  61. 61.
    Ye HF, O’Reilly KE, Koh JT 2001 A subtype-selective thyromimetic designed to bind a mutant thyroid hormone receptor implicated in resistance to thyroid hormone. J. Am. Chem. Soc. 123:1521–1522PubMedCrossRefGoogle Scholar
  62. 62.
    Ribeiro MO, Carvalho SD, Schultz JJ, et al. 2001 Thyroid hormone-sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoformspecific. Journal of Clinical Investigation 108:97–105PubMedGoogle Scholar
  63. 63.
    Furlow JD, Lim W, Ermio DJ, Chiellini G, Scanlan TS 2000 Molecular mechanisms underlying thyroid hormone induced gene expression cascades during amphibian metamorphosis. American Zoologist 40:1022–1023Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • John T. Koh
    • 1
  • Marc C. Putnam
    • 1
  1. 1.Department of Chemistry and BiochemistryUniversity of DelawareNewarkUSA

Personalised recommendations