Small-Molecule Immunostimulants. Synthesis and Activity of 7,8-Disubstituted Guanosines and Structurally Related Compounds

Reitz, Allen B.; Goodman, Michael; Pope, Barbara L.; Argentieri, Dennis; Bell, Stanley C.; Burr, L.; Chourmouzis, Erika; Come, Jon H.; Goodman, J H; Klaubert, Dieter H.

doi:10.1021/jm00047a014

Cited by 56 publications

(45 citation statements)

References 19 publications

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“…Indeed, long before the fact that these synthetic imidazoquinolines specifically engaged and activated TLR7 was known, it was recognized that these compounds were potently adjuvantic [96][97][98][99] in addition to displaying anti-viral effects via the induction of IFNγ. 100,101 In human blood stimulated ex vivo with TLR7 agonists, upregulation of the surface expression of costimulatory molecules such as CD40, CD80 and CD86 occurred in both CD11c…”

Section: -70mentioning

confidence: 99%

Immunoprofiling toll-like receptor ligands: Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models

et al. 2010

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Section: -70mentioning

confidence: 99%

Immunoprofiling toll-like receptor ligands: Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models

et al. 2010

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“…There is considerable interest in small molecule, non-polymeric (non ssRNA-derived), synthetic TLR7 agonists which include the imidazoquinolines [Imiquimod, Resiquimod (R-848) and Gardiquimod], [160][161][162] as well as guanosine analogues such as loxoribine [163][164][165] (Fig. 8).…”

Section: Intracellular Tlr7 Activation: Imidazoquinoline Ligandsmentioning

confidence: 99%

“…Long before the fact that these synthetic analogues specifically engaged and activated TLR7 was known, it was recognized that these compounds were potently adjuvantic [163][164][165][166][167][168][169] in addition to displaying anti-viral effects via the induction of IFNα/β. 143,162,170,171 It became apparent as early as 1991 that loxoribine (7-allyl 8-oxoguanosine) potentiated anti-tetanus-specific IgG antibody anamnestic responses in a dose-dependent manner in human peripheral blood Figure 7.…”

Section: Intracellular Tlr7 Activation: Imidazoquinoline Ligandsmentioning

confidence: 99%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…1) was studied in greatest detail and shown to exhibit broad spectrum antiviral activity and activate natural killer cells, macrophages, and B lymphocytes (20). Other guanosine analogs extensively studied were 7-deazaguanosine (21) and 7-allyl-8-oxoguanosine (loxoribine) (22). The exact mechanism of immune potentiation by these guanine derivatives has not been elucidated.…”

mentioning

confidence: 99%

Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7

Lee

Chuang

Redecke

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

526

420

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Certain C8-substituted and N7, C8-disubstituted guanine ribonucleosides comprise a class of small molecules with immunostimulatory activity. In a variety of animal models, these agents stimulate both humoral and cellular immune responses. The antiviral actions of these guanosine analogs have been attributed to their ability to induce type I IFNs. However, the molecular mechanisms by which the guanosine analogs potentiate immune responses are not known. Here, we report that several guanosine analogs activate Toll-like receptor 7 (TLR7). 7-Thia-8-oxoguanosine, 7-deazaguanosine, and related guanosine analogs ac- trihydrochloride)} were not inhibited by chloroquine, whereas TLR9 activation by CpG oligodeoxynucleotides was abolished. In summary, we present evidence that guanosine analogs activate immune cells via TLR7 by a pathway that requires endosomal maturation. Thus, the B cell-stimulating and antiviral activities of the guanosine analogs may be explained by their TLR7-activating capacity.

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Small-Molecule Immunostimulants. Synthesis and Activity of 7,8-Disubstituted Guanosines and Structurally Related Compounds

Cited by 56 publications

References 19 publications

Immunoprofiling toll-like receptor ligands: Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models

Immunoprofiling toll-like receptor ligands: Comparison of immunostimulatory and proinflammatory profiles in ex vivo human blood models

Potential adjuvantic properties of innate immune stimuli

Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7

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