Masked oral prodrugs of toll-like receptor 7 agonists: A new approach for the treatment of infectious disease

Current Opinion in Investigational Drugs

Volumn 7, Issue 8, 2006, Pages 702-708

  Fletcher, Simon ^a   Steffy, Kevin ^a   Averett, Devron ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

ANA 975; Hepatitis C virus; Interferon; Isatoribine; Toll like receptor 7

Indexed keywords

852A; 9 BENZYL 8 HYDROXY 2 (2 METHOXYETHOXY)ADENINE; ADENINE DERIVATIVE; ALPHA INTERFERON; ANA 975; ANTIVIRUS AGENT; BROPIRIMINE; IMIDAZOQUINOLINE DERIVATIVE; IMIQUIMOD; IMMUNOMODULATING AGENT; ISATORIBINE; LOXORIBINE; PATTERN RECOGNITION RECEPTOR; PRODRUG; RESIQUIMOD; RIBAVIRIN; SM 360320; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 7 AGONIST; UNCLASSIFIED DRUG;

ACTINIC KERATOSIS; ANTIVIRAL ACTIVITY; BASAL CELL CARCINOMA; CANCER; CELLULAR IMMUNITY; CHRONIC HEPATITIS; CLINICAL TRIAL; CONDYLOMA; DOSE RESPONSE; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG MARKETING; DRUG MEGADOSE; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; GASTROENTERITIS; GASTROINTESTINAL HEMORRHAGE; GASTROINTESTINAL TOXICITY; GENITAL HERPES; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; MASKING; MOLECULAR WEIGHT; NAUSEA; NONHUMAN; PAPILLOMA VIRUS; PROTEIN EXPRESSION; REVIEW; STRUCTURE ACTIVITY RELATION; SYSTEMATIC REVIEW; TREATMENT INDICATION; VIRUS INFECTION; VIRUS LOAD; VOMITING;

ADMINISTRATION, ORAL; AMINOQUINOLINES; ANIMALS; GUANOSINE; HEPATITIS C, CHRONIC; HUMANS; PRODRUGS; TOLL-LIKE RECEPTOR 7;

EID: 33747622584     PISSN: 14724472     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (68)

1. Akira S, Uematsu S, Takeuchi O: Pathogen recognition and innate immunity. Cell (2006) 124(4):783-801.
2. Zuany-Amorim C, Hastewell J, Walker C: Toll-like receptors as potential therapeutic targets for multiple diseases. Nat Rev Drug Discov (2002) 1(10):797-807.
3. Hoffman ES, Smith RE, Renaud RC Jr: From the analyst's couch: TLR-targeted therapeutics. Nat Rev Drug Discov (2005) 4(11):879-880.
4. van Duin D, Medzhitov R, Shaw AC: Triggering TLR signaling in vaccination. Trends Immunol (2006) 27(1):49-55.
5. Chuang TH, Ulevitch RJ: Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur Cytokine Netw (2000) 11(3):372-378.
6. Du X, Poltorak A, Wei Y, Beutler B: Three novel mammalian toll-like receptors: Gene structure, expression, and evolution. Eur Cytokine Netw (2000) 11(3):362-371.
7. Wagner H: The immunobiology of the TLR9 subfamily. Trends Immunol (2004) 25(7):381-386.
8. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science (2004) 303(5663):1529-1531.
9. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S: Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science (2004) 303(5663):1526-1529.
10. Kariko K, Buckstein M, Ni H, Weissman D: Suppression of RNA recognition by toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity (2005) 23(2):165-175.
11. Homung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, Endres S, Hartmann G: Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytold dendritic cells through TLR7. Nat Med (2005) 11(3):263-270.
12. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA: Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA (2004) 101(15):5598-5603.
13. Kato H, Sato S, Yoneyama M, Yamamoto M, Uematsu S, Matsui K, Tsujimura T, Takeda K, Fujita T, Takeuchi O, Akiara S: Cell type-specific involvement of RIG-I in antiviral response. Immunity (2005) 23(1):19-28.
14. Crozat K, Beutler B: TLR7: A new sensor of viral infection. Proc Natl Acad Sci USA (2004) 101(18):6835-6836.
15. Koski GK, Kariko K, Xu S, Weissman D, Cohen PA, Czemiecki BJ: Cutting edge: Innate Immune system discriminates between RNA containing bacterial versus eukaryotic structural features that prime for high-level IL-12 secretion by dendritic cells. J Immunol (2004) 172(7):3989-3993.
16. Zarember KA, Godowski PJ: Tissue expression of human toll-like receptors and differential regulation of toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol (2002) 168(2):554-561.
17. Nishimura M, Naito S: Tissue-specific mRNA expression profiles of human toll-like receptors and related genes. Biol Pharm Bull (2005) 28(5):886-892.
18. Liu YJ: IPC: Professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol (2005) 23:275-308.
19. Samuel CE: Antiviral actions of interferons. Clin Microbiol Rev (2001) 14(4):778-809.
20. Iwasaki A, Medzhitov R: Toll-like receptor control of the adaptive immune responses. Nat Immunol (2004) 5(10):987-995.
21. Hornung V, Schlender J, Guenthner-Biller M, Rothenfusser S, Endres S, Conzelmann KK, Hartmann G: Replication-dependent potent IFN-α induction in human plasmacytoid dendritic cells by a single-stranded RNA virus. J Immunol (2004) 173(10):5935-5943.
22. Nagahara K, Anderson JD, Kini GD, Dalley NK, Larson SB, Smee DF, Jin A, Sharma BS, Jolley WB, Robins RK et al: Thiazolo[4.5-d] pyrimidine nucleosides. The synthesis of certain 3-β-D-ribofuranosylthiazolo [4,5-d]pyrimidines as potential immunotherapeutic agents. J Med Chem (1990) 33(1):407-415.
23. Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E Cottam HB: Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of toll-like receptor 7. Proc Natl Acad Sci USA (2003) 100(11):6646-6651.
24. Bonnet PA, Robins RK: Modulation of leukocyte genetic expression by novel purine nucleoside analogues. A now approach to antitumor and antiviral agents. J Med Chem (1993) 36(6):635-653.
25. Reitz AB, Goodman MG, Pope BL, Argentieri DC, Bell SC, Burr LE, Chourmouzis E, Come J, Goodman JH, Klaubert DH et al: Small-molecule immunostimulants. Synthesis and activity of 7,8-disubstituted guanosines and structurally related compounds. J Med Chem (1994) 37(21):3561-3578.
26. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S: The toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol (2003) 33(11):2987-2997.
27. Stringfellow DA, Vanderberg HC, Weed SD: Interferon induction by 5-halo-6-phenyl pyrimidinones. J Interferon Res (1980) 1(1):1-14.
28. Takeda K, Kaisho T, Akira S: Toll-like receptors. Annu Rev Immunol (2003) 21:335-376.
29. Kurimoto A, Ogino T, Ichii S, Isobe Y, Tobe M, Ogita H, Takaku H, Sajiki H, Hirota K, Kawakami H: Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities. Bioorg Med Chem (2004) 12(5): 1091-1099.
30. Lee J, Wu CC, Lee KJ, Chuang TH, Katakura K, Liu YT, Chan M, Tawatao R, Chung M, Shen C, Cottam HB, Lai MM et al: Activation of anti-hepatitis C virus responses via toll-like receptor 7. Proc Natl Acad Sci USA (2006) 103(6):1828-1833.
31. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S: Small antiviral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol (2002) 3(2):196-200.
32. Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, Oesterich JL, Gorden KB, Qiu X, McKane SW, Noelle RJ et al: Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol (2002) 218(1-2):74-86.
33. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S: Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol (2002) 3(6):499.
34. 3M Pharmaceuticals: 3M provides update on IRM pharmaceutical platform: Lilly and 3M suspend resiquimod trials. Press Release (2003): February 24.
35. Dudek A, Yunis C, Kumar S, Harrison L, Hawkinson R, Miller J: Immune response activation by a toll-like receptor 7 agonist: Results of a phase 1 study. J Clin Oncol (2005) 23(suppl 16).A2515.
36. Skinner RB Jr: Imiquimod. Dermatol Clin (2003) 21(2):291-300.
37. Gupta AK, Browne M, Bluhm R: Imiquimod: A review. J Cutan Med Surg (2002) 6(6):554-560.
38. Gupta AK, Cherman AM, Tyring SK: Viral and nonviral uses of imiquimod: A review. J Cutan Med Surg (2004) 8(5):338-352.
39. Oldfield V, Keating GM, Perry CM: Imiquimod: In superficial basal cell carcinoma. Am J Clin Dermatol (2005) 6(3):195-200.
40. Spruance SL, Tyring SK, Smith MH, Meng TC: Appitcallon of a topical immune response modifier, resiquimod gel, to modify the recurrence rate of recurrent genital herpes: A pilot study. J Infect Dis (2001) 184(2):196-200.
41. Wu JJ, Huang DB, Tyring SK: Resiquimod: A new immune response modifier with potential as a vaccine adjuvant for Th1 immune responses. Antiviral Res (2004) 64(2):79-83.
42. Higgins PG, Barrow GI, Tyrell DA, Snell NJC, Jones K, Jolley WB: A study of the efficacy of the immunomodulatory compound 7-thia-8-oxoguanosine in coronavirus 229E infections in human volunteers. Antiviral Chem Chemother (1991) 2:61-63.
43. Witt PL, Ritch PS, Reding D, McAuliffe TL, Westrick L, Grossberg SE, Borden EC: Phase I trial of an oral immunomodulator and interferon inducer in cancer patients. Cancer Res (1993) 53(21):5176-5180.
44. Savage P, Horton V, Moore J, Owens M, Witt P, Gore ME: A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. Br J Cancer (1998) 74(9):1482-1486.
45. Witjes JA: Treatment of carcinoma in situ of the urinary bladder with bropirimine. Eur Urol (1997) 31(Suppl 1):27-30.
46. Wtjes WP, Konig M, Boeminghaus FP, Hall RR, Schulman CC, Zurlo M, Fittipaldo A, Riggi M, Debruyne FM: Results of a European comparative randomized study comparing oral bropirimine versus intravesical BCG treatment in BCG-naive patients with carcinoma in situ of the urinary bladder. European Bropirimine Study Group. Eur Urol (1999) 36(6):576-581.
47. Abreu MT, Fukata M, Arditi M: TLR signaling in the gut in health and disease. J Immunol (2005) 174(8):4453-4460.
48. Strader DB, Wright T, Thomas DL, Seeff LB: Diagnosis, management, and treatment of hepatitis C. Hepatology (2004) 39(4):1147-1171.
49. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A et al: Peginterferon α-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med (2002) 347(13).975-982.
50. Smee DF, Alaghamandan HA, Cottam HB, Sharma BS, Jolley WB, Robins RK: Broad-spectrum in vivo antiviral activity of 7-thia-8-oxoguanosine, a novel immunopotentlating agent Antimicrob Agents Chemother (1989) 33(9):1487-1492.
51. Smee DF, Alaghamandan HA, Cottam HB, Jolley WB, Robins RK: Antiviral activity of the novel immune modulator 7-thia-8-oxoguanosine. J Biol Response Mod (1990) 9(1):24-32.
52. Smee DF, Huffman JH, Gessaman AC, Huggins JW, Sidwell RW: Prophylactic and therapeutic activities of 7-thia-8-oxoguanosine against Punta Toro virus infections in mice. Antiviral Res (1991) 15(3):229-239.
53. Smee DF, Alaghamandan HA, Gilbert J, Burger RA, Jin A, Sharma BS, Ramasamy K, Revankar GR, Cottam HB, Jolley WB, Robins RK: Immunoenhancing properties and antiviral activity of 7-deazaguanosine in mice. Antimicrob Agents Chemother (1991) 35(1):152-157.
54. De Clercq E: Antiviral drugs in current clinical use. J Clin Virol (2004) 30(2):115-133.
55. Horsmans Y, Berg T, Desager JP, Mueller T, Schott E, Fletcher SP, Steffy KR, Bauman LA, Kerr BM, Averett DR: Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatol (2005) 42(3):724-731.
56. Bruno R, Sacchi P, Ciappina V, Zochetti C, Patruno S, Maiocchi L, Filice G: Viral dynamics and pharmacokineties of peginterferon α-2a and peginterferon α-2b in naive patients with chronic hepatitis C: A randomized, controlled study. Antivir Ther (2004) 9(4):491-497.
57. Buti M, Sanchez-Avila F, Lurie Y, Stalgis C, Valdes A, Martell M, Esteban R: Viral kinetics in genotype 1 chronic hepatitis C patients during therapy with 2 different doses of peginterferon α-2b plus ribavirin. Hepatol (2002) 35(4):930-936.
58. Glue P, Fang JW, Rouzier-Panis R, Raffanell C, Sabo R, Gupta SK, Salfi M, Jacobs S: Pegylated interferon-α2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther (2000) 68(5):556-567.
59. Herrmann E, Lee JH, Marinos G, Modi M, Zeuzem S: Effect of ribavirin on hepatitis C viral kinetics in patients treated with pegylated interferon. Hepatology (2003) 37(6):1351-1358.
60. Pockros P, Tong M, Wright T: A phase IIa placebo-controlled double-blind trial to determine the safety, tolerability, PK/PD of an oral interferon inducer, resiquimod, in chronic HCV. Gastroenterol (2003) 124(Supp 1)A766.
61. Kerr B, Bauman L, Webber S, Xiang A, Ng J, Kirkovsky L, Bartkowski D, Steffy K, Fletcher S, Aust R, Theiss J et al: Pharmacokinetics, safety and tolerability of the isatoribine oral prodrug ANA976 in a phase 1 healthy volunteer study. Hepatol (2005) 42(Suppl 1):A533.
62. Isogawa M, Robek MD, Furuichi Y, Chisari FV: Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol (2005) 79(11):7269-7272.
63. Arevalo I, Ward B, Miller R, Meng TC, Najar E, Alvarez E, Matlashewski G, Llanos-Cuentas A: Successful treatment of drug-resistant cutaneous leishmaniasis in humans by use of imiquimod, an immunomodulator. Clin Infect Dis (2001) 33(11):1847-1851.
64. Morrey JD, Day CW, Julander JG, Blatt LM, Smee DF, Sidwell RW: Effect of interferon-α and interferon-inducers on West Nile virus in mouse and hamster animal models. Antivir Chem Chemother (2004) 15(2):101-109.
65. Stokes JR, Sorkness RL, Kaplan MR, Castleman WL, Tomai MA, Miller RL, Lemanske RF Jr: Attenuation of virus-induced airway dysfunction in rats treated with imiquimod. Eur Respir J (1998) 11(2):324-329.
66. Chen M, Griffith BP, Lucia HL, Hsiung GD: Efficacy of S26308 against guinea pig cytomegalovirus infection. Antimicrob Agents Chemother (1988) 32(5):678-683.
67. Kende M, Lupton H, Canonico P: Treatment of experimental viral infections with immunomodulators. Adv Biosci (1988) 68:51-63.
68. Amlie-Lefond C, Paz DA, Connelly MP, Huffnagle GB, Dunn KS, Whelan NT, Whelan HT: Innate immunity for biodefense: A strategy whose time has come. J Allergy Clin Immunol (2005) 116(6):1334-1342.