|
|
Development of Potential Therapeutics Targeting to Human Toll-like Receptor |
|
|
Abstract There is a growing interest in the targeting of toll-like receptors (TLRs), a kind of pathogen-associated molecular patterns. TLRs activate NF-?B pathway, regulate the secretion of cytokines such as TNF-?, ILs and IFN-?, and ultimately improve the function of immunity system. Over ten TLRs have been discovered in human genome that may be the therapy targets for cancer, viral and bacterial infection, inflammation, autoimmunity and radiation injury. Several compounds targeting TLRs are now undergoing preclinical or clinical evaluation, including anti-tumor drugs, anti-virus drugs, anti-infection drugs and anti-radiation drugs. This review summarized the structural feature of TLRs, the characteristics of their signaling pathways, the develop status of related compounds and analyzed further possibilities for therapeutic manipulation.
|
Received: 10 June 2010
Published: 19 October 2010
|
Corresponding Authors:
Zhongbin Chen
E-mail: chenzb@bmi.ac.cn
|
|
|
[1] Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature immunology, 2010, 11(5): 373~384
[2] Hennessy E J, Parker A E, O’Neill L A. Targeting Toll-like receptors: emerging therapeutics? Drug discovery, 2010, 9(4): 293~306
[3] Shigeoka A A, Holscher T D, King A J, et al. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. J. Immunol, 2007, 178 (10): 6252~6258
[4] Yamamoto M, Sato S, Hemmi H, et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol, 2003, 4 (11): 1144~1150
[5] Yamamoto M, Sato S, Hemmi H, et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature, 2002, 420 (6913): 324~329
[6] Shokouhi B, Coban C, Hasirci V, et al. The role of multiple toll-like receptor signalling cascades on interactions between biomedical polymers and dendritic cells. Biomaterials. 2010, 31(22): 5759~5771
[7] Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol, 2002, 3(2): 196~200
[8] Dummer R, Hauschild A, Becker J C, et al. An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. Clin Cancer Res, 2008, 14(3): 856~864
[9] Panter G, Kuznik A, Jerala R. Therapeutic applications of nucleic acids as ligands for Toll-like receptors. Curr. Opin. Mol. Ther, 2009, 11(2), 133~145
[10] Agrawal S, Kandimalla E R. Synthetic agonists of Toll-like receptors 7, 8 and 9. Biochem. Soc. Trans, 2007, 35(Pt6): 1461~1467
[11] Kochling, J. Prada J, Bahrami M, et al. Anti-tumor effect of DNA-based vaccination and dSLIM immunomodulatory molecules in mice with Ph+ acute lymphoblastic leukaemia. Vaccine, 2008, 26(36): 4669~4675
[12] Chin AI, Miyahira A K, Covarrubias A, et al.Toll-like receptor 3-mediated suppression of TRAMP prostate cancer shows the critical role of type I interferons in tumor immune surveillance. Cancer Res, 2010, 70(7): 2595~603
[13] Garay R P, Viens P, Bauer J, et al. Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur J Pharmacol, 2007, 563(1-3): 1~17
[14] Simons M P, O’Donnell M A, Griffith T S. Role of neutrophils in BCG immunotherapy for bladder cancer. Urol. Oncol, 2008, 26(4): 341~345
[15] Parkinson T. The future of toll-like receptor therapeutics. Curr. Opin. Mol. Ther, 2008, 10(1): 21~31
[16] Kronenberger B, Zeuzem S. Current and future treatment options for HCV. Ann. Hepatol, 2009, 8(2): 103~112
[17] Casella C R, Mitchell T C. Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell. Mol. Life Sci, 2008, 65(20): 3231~3340
[18] Nardo D, Nardo C M, Nguyen T, et al. Signaling crosstalk during sequential TLR4 and TLR9 activation amplifies the inflammatory response of mouse macrophages. J Immunol, 2009, 183(12): 8110~8118
[19] Klouwenberg K P, Tan L, Werkman W, et al. The role of Toll-like receptors in regulating the immune response against respiratory syncytial virus. Crit Rev Immunol, 2009, 29(6): 531~550
[20] Kanzler H, Barrat F J, Hessel E M, et al. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nature Med, 2007, 13(5): 552~559
[21] Ramaprakash H, Hogaboam C M. Intranasal CpG therapy attenuated experimental fungal asthma in a TLR9-dependent and -independent manner. Int Arch Allergy Immunol, 2010, 152(2): 98~112
[22] Rosewich M P. Ultra-short course immunotherapy in children and adolescents during a 3-yrs post-marketing surveillance study. Pediatr Allergy Immunol, 2010, 21: e185~e189
[23] Gowen B B, Wong M H, Jung K H. Tlr3 is essential for the induction of protective immunity against Punta Toro virus infection by the double-stranded RNA (dsRNA), poly(I:C12U), but not poly(I:C): Differential recognition of synthetic dsRNA molecules. J. Immunol, 2007, 282(8): 11817~11826
[24] Lu Zh W. Potential therapeutic interventions on toll like receptors for clinical applications. Research in pharmaceutical biotechnology, 2010, 2(1): 7~13
[25] Wasan K M, Risovic V, Sivak O, et al. Influence of plasma cholesterol and triglyceride concentrations and eritoran (E5564) micelle size on its plasma pharmacokinetics and ex vivo activity following single intravenous bolus dose into healthy female rabbits. Pharm. Res, 2008, 25(1): 176~182
[26] Chang Y C, Kao W C, Wang W Y, et al. Identification and characterization of oligonucleotides that inhibit Toll-like receptor2-associated immune responses. FASEB J, 2009, 23(9): 3078~3088
[27] Burdelya L G, Krivokrysenko V I, Tallant T C, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science, 2008, 320(5873): 226~230
[28] Sfondrini L, Rossini A, Besusso D, et al. Antitumor activity of the TLR-5 ligand flagellin in mouse models of cancer. J. Immunol, 2006, 176(11): 6624~6630
[29] Medzhitov R, Janeway C Jr. The Toll receptor family and microbial recognition. Trends Microbiol, 2000, 8(10): 452~456
[30] Huleatt J W, Nakaar V, Desai P, et al. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine, 2008, 26(2): 201~214
[31] Sheedy F J, O’Neill L A. Adding fuel to fire: microRNAs as a new class of mediators of inflammation. Ann. Rheum. Dis, 2008, 67 (Suppl. 3): 50~55
[32] Koziczak-Holbro M, Littlewood-Evans A, P?llinger B, et al. The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation. Arthritis Rheum, 2009, 60(6): 1661~1671
[33] Kawagoe T, Sato S, Matsushita K, et al. Sequential control of Toll-like receptordependent responses by IRAK1 and IRAK2. Nature Immunol, 2008, 9(6): 684~691
[34] Tsung, A. McCoy S L, Klune J R, et al. A novel inhibitory peptide of Toll-like receptor signaling limits lipopolysaccharide-induced production of inflammatory mediators and enhances survival in mice. Shock, 2007, 27(4): 364~369
|
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
|
Shared |
|
|
|
|
|
Discussed |
|
|
|
|