Immunosuppressant discovery from Tripterygium wilfordii Hook f: The novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8)

Acta Pharmacologica Sinica

Volumn 33, Issue 9, 2012, Pages 1112-1118

  Tang, Wei ^a   Zuo, Jian Ping ^a  

^a SHANGHAI INSTITUTE OF MATERIA MEDICA   (China)

Author keywords

(5R) 5 hydroxytriptolide (LLDT 8); autoimmune diseases; clinical trials; immunosuppressants; Tripterygium wilfordii Hook f; triptolide

Indexed keywords

IMMUNOSUPPRESSIVE AGENT; LLDT 8; TRIPTOLIDE; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; AUTOIMMUNE DISEASE; DISEASE SEVERITY; HUMAN; IC 50; IMMUNE RESPONSE; INFLAMMATORY DISEASE; LYMPHOCYTE PROLIFERATION; MACROPHAGE ACTIVATION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; TRIPTERYGIUM WILFORDII;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ARTHRITIS, RHEUMATOID; AUTOIMMUNE DISEASES; DITERPENES; DRUG DESIGN; DRUGS, CHINESE HERBAL; HUMANS; IMMUNOSUPPRESSIVE AGENTS; INFLAMMATION; PLANT EXTRACTS; SOLUBILITY; TRIPTERYGIUM;

EID: 84865964525     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1038/aps.2012.108     Document Type: Review

References (67)

1. Drug discovery from Nature. Susanne Grabley, Ralf Thiericke. ISBN 3-540-64844-5 Springer-Verlag Berlin Heidelberg New York.
2. Paterson I, Anderson EA. The renaissance of natural products as drug candidates. Science 2005; 310: 451-3. (Pubitemid 41507948)
3. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 2005; 4: 206-20 . (Pubitemid 40372555)
4. Ganesan A. The impact of natural products upon modern drug discovery. Curr Opin Chem Biol 2008; 123: 306-17.
5. Newman DJ, Cragg GM, Snader KM . The influence of natural products upon drug discovery. Nat Prod Rep 2000; 17: 215-34 . (Pubitemid 30390787)
6. Oxford AE, Raistrick H. Studies in the biochemistry of microorganisms: 3:5-Dihydroxyphthalic acid, a new product of the metabolism of glucose by Penicillium brevi-compactum and related species. Biochem J 1932; 26: 1902-6.
7. Petcher TJ, Weber H, Rüegger A. Crystal and molecular structure of an iodo-derivative of the cyclic undecapeptide cyclosporin A. Helv Chim Acta 1976; 14; 59: 1480-9.
8. Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 1975; 28: 721-6.
9. Ochiai T, Nakajima K, Nagata M, Hori S, Asano T, Isono K. Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats. Transplantation 1987; 44: 734-8. (Pubitemid 18034269)
10. Ochiai T, Nagata M, Nakajima K, Suzuki T, Sakamoto K, Enomoto K, et al. Studies of the effects of FK506 on renal allografting in the beagle dog. Transplantation 1987; 44: 729-33. (Pubitemid 18034268)
11. Adachi K, Kohara T, Nakao N, Aritac M, Chibac K, Mishina T, et al. Design, synthesis and structure-activity relationships of 2-substituted 2-amino-1,3-propanediols: Discovery of a novel immunosuppressant, FTY720. Bioorg Med Chem Lett 1995; 5: 853-6.
12. Li JW, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science 2009; 325: 161-5.
13. Allison AC. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 2000; 47: 63-83. (Pubitemid 30394533)
14. Tao X, Davis LS, Lipsky PE. Effect of an extract of the Chinese herbal remedy Tripterygium wilfordii Hook F on human immune responsiveness. Arthritis Rheum 1991; 34: 1274-81.
15. Asano K, Matsuishi J, Yu Y, Kasahara T, Hisamitsu T. Suppressive effects of Tripterygium wilfordii Hook f, a traditional Chinese medicine, on collagen arthritis in mice. Immunopharmacology 1998; 39: 117-26. (Pubitemid 28321512)
16. Gu WZ, Brandwein SR. Inhibition of type II collagen-induced arthritis in rats by triptolide. Int J Immunopharmacol 1998; 20: 389-400. (Pubitemid 29034723)
17. Gu WZ, Banerjee S, Rauch J, Brandwein SR. Suppression of renal disease and arthritis, and prolongation of survival in MRL-lpr mice treated with an extract of Tripterygium wilfordii Hook f. Arthritis Rheum 1992; 35: 1381-6.
18. Gu WZ, Brandwein SR, Banerjee S. Inhibition of type II collagen induced arthritis in mice by an immunosuppressive extract of Tripterygium wilfordii Hook f. J Rheumatol 1992; 19: 682-8.
19. Asano K, Yu Y, Kasahara T, Hisamitsu T. Inhibition of murine chronic graft-versus-host disease by the chloroform extract of Tripterygium wilfordii Hook f. Transpl Immunol 1997; 5: 315-9. (Pubitemid 28026577)
20. Wang J, Xu R, Jin R, Chen Z, Fidler JM. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii: II. Prolongation of hamster-to-rat cardiac xenograft survival by combination therapy with the PG27 extract and cyclosporine. Transplantation 2000; 70: 456-64. (Pubitemid 30641500)
21. Tao X, Cush JJ, Garret M, Lipsky PE. A phase I study of ethyl acetate extract of the chinese antirheumatic herb Tripterygium wilfordii hook F in rheumatoid arthritis. J Rheumatol 2001; 28: 2160-7. (Pubitemid 32947856)
22. Goldbach-Mansky R, Wilson M, Fleischmann R, Olsen N, Silverfield J, Kempf P, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial. Ann Intern Med 2009; 151: 229-40, W49-51.
23. Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum 2002; 46: 1735-43. (Pubitemid 34774504)
24. Cibere J, Deng Z, Lin Y, Ou R, He Y, Wang Z, et al. A randomized double blind, placebo controlled trial of topical Tripterygium wilfordii in rheumatoid arthritis: reanalysis using logistic regression analysis J Rheumatol 2003; 30: 465-7. (Pubitemid 36301935)
25. Marks WH. Tripterygium wilfordii Hook F. versus Sulfasalazine in the treatment of rheumatoid arthritis: a well-designed clinical trial of a botanical demonstrating effectiveness. Fitoterapia 2011; 82: 85-7.
26. Jiang X. Clinical observations on the use of the Chinese herb Tripterygium wilfordii Hook for the treatment of nephrotic syndrome. Pediatr Nephrol 1994; 8: 343-4. (Pubitemid 24162277)
27. Han R, Rostami-Yazdi M, Gerdes S, Mrowietz U. Triptolide in the treatment of psoriasis and other immune-mediated inflammatory diseases. Br J Clin Pharmacol 2012; 74: 424-36.
28. Harousseau JL, Dombret H, Pigneux A, Michallet M, Brandely M. Phase I study of F60008, a triptolide derivative, in patients with refractory or relapsing acute leukemias. 13th Congress of the European Hematology Association (EHA); 2008: 2008.
29. Kitzen JJ, de Jonge MJ, Lamers CH, Eskens FA, van der Biessen D, van Doorn L, et al. Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. Eur J Cancer 2009; 45: 1764-72.
30. Liu J, Chen X, Zhang Y, Miao H, Liu K, Li L, et al. Derivatization of (5R)-hydroxytriptolide from benzylamine to enhance mass spectrometric detection: application to a Phase I pharmacokinetic study in humans. Anal Chim Acta 2011; 689: 69-76.
31. Zhou R, Zhang F, He PL, Zhou WL, Wu QL, Xu JY, et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol 2005; 5: 1895-903. (Pubitemid 41586228)
32. Tang W, Yang Y, Zhang F, Li YC, Wang JX, Zhu YN, et al. Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells. Int Immunopharmacol 2005; 5: 1904-13. (Pubitemid 41586229)
33. Zhou R, Tang W, Ren YX, He PL, Zhang F, Fu YF, et al. (5R)-5-hydroxytriptolide (LLDT-8) prevented collagen-induced arthritis in DBA/1 mice via suppressing IFN-? production and its related signaling. J Pharmacol Exp Ther 2006; 318: 35-44.
34. Zhou R, Wang JX, Tang W, He PL, Yang YF, Li YC, et al. (5R)-5-hydroxytriptolide inhibits IFN-gamma-related signaling. Acta Pharmacol Sin 2006; 27: 1616-21.
35. Zhou R, Zheng SX, Tang W, He PL, Li XY, Yang YF, et al. Inhibition of inducible nitric-oxide synthase expression by (5R)-5-hydroxytriptolide (LLDT-8) in interferon-? and bacterial lipopolysaccharide stimulated macrophages. J Pharmacol Exp Ther 2006; 316: 121-8. (Pubitemid 41832588)
36. Fu YF, Zhu YN, Ni J, Zhong XG, Tang W, Zhou R, et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, prevents experimental autoimmune encephalomyelitis via inhibiting T cell activation. J Neuroimmunol 2006; 175: 142-51. (Pubitemid 43786227)
37. Zhou R, Tang W, Ren YX, He PL, Yang YF, Li YC, et al. Preventive effects of (5R)-5-hydroxytriptolide on concanavalin A-induced hepatitis. Eur J Pharmacol 2006; 537: 181-9.
38. Tang W, Yang Y, Zhou R, Li YC, Wang JX, Yang YF, et al. (5R)-5-hydroxytriptolide (LLDT-8), a potential inhibitor of chemokine, prevents allograft rejection in full MHC-mismatched mouse cardiac transplantation. Transplantation 2006; 81: 927-33.
39. Ren YX, Zhou R, Tang W, Wang WH, Li YC, Yang YF, et al. (5R)-5-hydroxytriptolide (LLDT-8) protects against bleomycin-induced lung fibrosis in mice. Acta Pharmacol Sin 2007; 28: 518-25. (Pubitemid 46496079)
40. Zhou R, Tang W, He PL, Ren YX, Yang YF, Li YC, et al. (5R)-5-hydroxytriptolide inhibits the immune response of human peripheral blood mononuclear cells. Int Immunopharmacol 2009; 9: 63-9.
41. Chan MA, Kohlmeier JE, Branden M, Jung M, Benedict SH. Triptolide is more effective in preventing T cell proliferation and interferongamma production than is FK506. Phytother Res 1999; 13: 464-7. (Pubitemid 29445761)
42. Gu WZ, Chen R, Brandwein S, McAlpine J, Burres N. Isolation, purification, and characterization of immunosuppressive compounds from tripterygium: triptolide and tripdiolide. Int J Immunopharmacol 1995; 17: 351-6.
43. Kupchan SM, Court WA, Dailey RG Jr, Gilmore CJ, Bryan RF. Triptolide and tripdiolide, novel antileukemic diterpenoid triepoxides from Tripterygium wilfordii. J Am Chem Soc 1972; 94: 7194-5.
44. Lin N, Liu C, Xiao C, Jia H, Imada K, Wu H, et al. Triptolide, a diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis mice. Biochem Pharmacol 2007; 73: 136-46. (Pubitemid 44872877)
45. Wang Y, Wei D, Lai Z, Le Y. Triptolide inhibits CC chemokines expressed in rat adjuvant-induced arthritis. Int Immunopharmacol 2006; 6: 1825-32. (Pubitemid 44574490)
46. Li R, Takazawa K, Suzuki H, Hariya A, Yamamoto T, Matsushita S, et al. Synergistic effect of triptolide and tacrolimus on rat cardiac allotransplantation. Jpn Heart J 2004; 45: 657-65. (Pubitemid 41518870)
47. Liu Y, Chen Y, Liu FQ, Lamb JR, Tam PK. Combined treatment with triptolide and rapamycin prolongs graft survival in a mouse model of cardiac transplantation. Transpl Int 2008; 21: 483-94. (Pubitemid 351490170)
48. Tao X, Davis LS, Hashimoto K, Lipsky PE. The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. J Pharmacol Exp Ther 1996; 276: 316-25. (Pubitemid 26151545)
49. Yang SX, Gao HL, Xie SS, Zhang WR, Long ZZ. Immunosuppression of triptolide and its effect on skin allograft survival. Int J Immunopharmacol 1992; 14: 963-9.
50. Lu H, Hachida M, Enosawa S, Li XK, Suzuki S, Koyanagi H. Immunosuppressive effect of triptolide in vitro. Transplant Proc 1999; 31: 2056-7. (Pubitemid 29376525)
51. Chen BJ. Triptolide, a novel immunosuppressive and antiinflammatory agent purified from a Chinese herb Tripterygium wilfordii Hook F. Leuk Lymphoma 2001; 42: 253-65. (Pubitemid 32725582)
52. Fidler JM, Ku GY, Piazza D, Xu R, Jin R, Chen Z. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. III. Suppression of graft-versus-host disease in murine allogeneic bone marrow transplantation by the PG27 extract. Transplantation 2002; 74: 445-57. (Pubitemid 34977671)
53. Ren J, Tao Q, Wang X, Wang Z, Li J. Efficacy of T2 in active Crohn's disease: a prospective study report. Dig Dis Sci 2007; 52: 1790-7. (Pubitemid 47024677)
54. Ji SM, Wang QW, Chen JS, Sha GZ, Liu ZH, Li LS. Clinical trial of Tripterygium Wilfordii Hook F in human kidney transplantation in China. Transplant Proc 2006; 38: 1274-9.
55. Wang J, Xu R, Jin R, Chen Z, Fidler JM. Immunosuppressive activity of the Chinese medicinal plant Tripterygium wilfordii. I. Prolongation of rat cardiac and renal allograft survival by the PG27 extract and immunosuppressive synergy in combination therapy with cyclosporine. Transplantation 2000; 70: 447-55. (Pubitemid 30641499)
56. Huynh PN, Hikim AP, Wang C, Stefonovic K, Lue YH, Leung A, et al. Long-term effects of triptolide on spermatogenesis, epididymal sperm function, and fertility in male rats. J Androl 2000; 21: 689-99.
57. Hikim AP, Lue YH, Wang C, Reutrakul V, Sangsuwan R, Swerdloff RS. Posttesticular antifertility action of triptolide in the male rat: evidence for severe impairment of cauda epididymal sperm ultrastructure. J Androl 2000; 21: 431-7. (Pubitemid 30252515)
58. Lue Y, Sinha Hikim AP, Wang C, Leung A, Baravarian S, Reutrakul V, et al. Triptolide: A potential male contraceptive. J Androl 1998; 19: 479-86. (Pubitemid 28397133)
59. Chen BJ, Liu C, Cui X, Fidler JM, Chao NJ. Prevention of graft-versushost disease by a novel immunosuppressant, PG490-88, through inhibition of alloreactive T cell expansion. Transplantation 2000; 70: 1442-7.
60. Crews GM, Erickson L, Pan F, Fisniku O, Jang MS, Wynn C, et al. Down-regulation of TGF-beta and VCAM-1 is associated with successful treatment of chronic rejection in rats. Transplant Proc 2005; 37: 1926-8. (Pubitemid 40790871)
61. Chen G, Sun H, Arp J, Garcia B, Wang X, Wise Y, et al. A synergistic effect between PG490-88 and tacrolimus prolongs renal allograft survival in monkeys. Am J Transplant 2006; 6: 714-23. (Pubitemid 43345009)
62. Wang X, Sun H, Chen G, Liu W, Wise Y, Yung C, et al. Immunosuppression with a combination of pg490-88 and a subtherapeutic dose of FK506 in a canine renal allograft model. Transplantation 2005; 79: 1537-44. (Pubitemid 40847585)
63. Fisniku O, Pan F, Wynn C, Erickson LM, Crews G, Jang MS, et al. Protective effects of PG490-88 on chronic allograft rejection by changing intragraft gene expression profiles. Transplant Proc 2005; 37: 1962-4. (Pubitemid 40790883)
64. Pan F, Fisniku O, Wynn C, Erickson LM, Crews G, Jang MS, et al. PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts. Transplant Proc 2005; 37: 134-6. (Pubitemid 40459714)
65. Leonard CT, Soccal PM, Berry GJ, Doyle RL, Theodore J, Duncan SR, et al. PG490-88, a derivative of triptolide, attenuates obliterative airway disease in a mouse heterotopic tracheal allograft model. J Heart Lung Transplant 2002; 21: 1314-8. (Pubitemid 35477747)
66. Chen BJ, Chen Y, Cui X, Fidler JM, Chao NJ. Mechanisms of tolerance induced by PG490-88 in a bone marrow transplantation model. Transplantation 2002; 73: 115-21. (Pubitemid 34094697)
67. Krishna G, Liu K, Shigemitsu H, Gao M, Raffin TA, Rosen GD. PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis. Am J Pathol 2001; 158: 997-1004. (Pubitemid 32221791)