Protective activity of the lipid A analogue GLA-60 against murine cytomegalovirus infection in immunodeficient mice

Ikeda, Satoru; Neyts, Johan; Matsuura, Motohiro; Kiso, Makoto; Hasegawa, Akira; Nishimura, Chiaki; Clercq, Erik De

doi:10.1099/0022-1317-74-7-1399

Cited by 7 publications

(3 citation statements)

References 29 publications

(20 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have been studying the biological activities of monosaccharide-type lipid A analogues and have shown that these analogues are nonpyrogenic but that some of them preserve LPS-mimetic activities such as induction of cytokines from murine macrophages (6,21,28) and induction of resistance to microbial infections and tumors in animal models (13,14,25,31). In these monosaccharide lipid A analogues, acylation patterns as well as phosphorylation patterns were revealed to play an important role in the expression of biological activities, as was observed for disaccharide lipid A analogues (34).…”

mentioning

confidence: 99%

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

1999

View full text Add to dashboard Cite

The lipid A portion of bacterial lipopolysaccharide (LPS) plays a central role in the production of endotoxic mediators. Different responses between human and murine macrophages to lipid A-like structures have been indicated. We investigated a series of structurally related monosaccharide lipid A analogues for their potency to activate human macrophage U937 cells and peripheral blood mononuclear cells for production of tumor necrosis factor-␣ and interleukin-6 compared with their potency to activate murine macrophage RAW264.7 cells. Two of the analogues were found to have sufficient potency to activate the human cells as well as the murine cells. These analogues comprise D-glucosamine, phosphoryl groups, and acyl groups of defined carbon chain lengths (C 14 and C 12 ) in a ratio of 1:1:3. This ratio of molecular constituents is proportional to that of the complete disaccharide structure of lipid A (2:2:6). Other analogues with two or four C 14 acyl groups and with three acyl groups but including a C 10 or a C 16 acyl group, which are active to murine cells, showed no LPS-agonistic activity, but did show LPS-antagonistic activity, to human cells. An LPS-antagonistic analogue in the murine cells also showed antagonistic activity in human cells. These results reveal that lipid A analogues recognized as being LPS agonists by human macrophages have common structural features in monosaccharide and disaccharide structures which are more strict than those required for recognition by murine macrophages and that broad lipid A-like structures are recognized as being LPS antagonists by human cells but are recognized by murine cells as being either LPS agonists or antagonists. by guest http://iai.asm.org/ Downloaded from FIG. 6. Structures of synthetic lipid A analogues in relation to their LPS-agonistic and -antagonistic actions in murine and human macrophages (M).

show abstract

mentioning

confidence: 99%

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

1999

View full text Add to dashboard Cite

show abstract

“…We suggested that macrophages, together with functional B and T cells, are essential in the host defense induced by GLA-60 against MCMV infection. Lipid A analogues differ from poly I:C in that (i) lipid A analogues have stronger macrophage-stimulating effect than poly I:C, and (ii) poly I:C is superior to lipid A analogues as IFN inducer and NK-cell stimulator (26,27,30,31).…”

Section: Discussionmentioning

confidence: 98%

Host Defense Mechanisms Against Murine Cytomegalovirus Infection Induced by Poly l:C in Severe Combined Immune Deficient (SCID) Mice

Ikeda

Neyts

Clercq

1994

Experimental Biology and Medicine

Self Cite

View full text Add to dashboard Cite

The role of host defense mechanism against murine cytomegalovirus (MCMV) infection in mice with severe combined immunodeficiency (SCID) was investigated using polyinosinic:polycytidylic acid (poly I:C) as a nonspecific stimulator of the immune system. When administered ip at doses of 3.7 or 15 mg/kg 18 hr prior to infection of SCID mice with 10(3) or 10(4) plaque-forming units of MCMV, poly I:C significantly increased the animals' life span. Poly I:C enhanced, in a dose-dependent manner (0.01-1 mg/kg), the peritoneal natural killer (NK)-cell activity and macrophage activity of SCID mice. When SCID mice were pretreated with anti-asialo GM1 antibody (against NK cells) or anti-Mac1 antibody (against macrophages), poly I:C failed to stimulate the activity of NK cells and macrophages. Intraperitoneal administration of poly I:C also induced both early (2 hr) and late (18 hr) type interferon (IFN) in the peritoneal fluid and blood. The IFN-inducing activity of polyl:C was not affected by pretreatment of the mice with anti-asialo GM1 or anti-Mac1 antibody. Poly I:C also caused a significant but less pronounced increase in the life span of MCMV-infected SCID mice in which the NK cells or macrophages had been depleted by treatment with anti-asialo GM1 or anti-Mac1 antibody, respectively. These results suggest that poly I:C-induced interferon as well as activation of NK cell and macrophages contribute to the host defense mechanism against MCMV infection in SCID mice.

show abstract

“…For example, GLA-60 (27, Fig. 3) showed the strongest B-cell activation and adjuvant activities among various non-reducing subunit analogs that have been examined [47] and has been shown to non-specifically protect mice against cytomegalovirus virus [53]. SAR investigations showed the importance of normal fatty acid chain length, stereochemistry, and the number, type and relative position of the fatty acyl moieties in this series.…”

Section: Monosaccharide Mimetics Of S Minnesota Lipid Amentioning

confidence: 99%

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

Johnson¹

2008

CTMC

View full text Add to dashboard Cite

The design of vaccine adjuvants and stand-alone immunotherapeutics has historically been a mix of alchemy and accident partly because of the complex nature of the molecular mechanisms involved in immune system function. The recent discovery of pattern recognition receptors and toll-like receptors (TLRs) in particular on cells of the immune system has shown the important role that stimulation of these cell receptors by microbial products plays in both innate and adaptive immune responses. Considerable effort has been directed at developing pharmaceutically acceptable mimetics of many TLR-active natural products, including the main cell-surface component of Gram-negative bacteria: lipopolysaccharide (LPS). LPS and its active principle, lipid A, are potent stimulators of host defense systems via their interaction with TLR4. However, the profound pyrogenicity and lethal toxicity of LPS and lipid A have precluded their medicinal use. Structure/activity investigations on natural S. minnesota R595 lipid A and its derivatives have led to the development of a novel class of synthetic lipid A mimetics known as aminoalkyl glucosaminide phosphates (AGPs). This review discusses the evolution of the AGPs and related TLR4-active glycolipids with emphasis on structure/activity relationships in the AGP series and pre-clinical/clinical development of selected AGPs, including the potent vaccine adjuvant RC-529.

show abstract

Protective activity of the lipid A analogue GLA-60 against murine cytomegalovirus infection in immunodeficient mice

Cited by 7 publications

References 29 publications

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

Activity of Monosaccharide Lipid A Analogues in Human Monocytic Cells as Agonists or Antagonists of Bacterial Lipopolysaccharide

Host Defense Mechanisms Against Murine Cytomegalovirus Infection Induced by Poly l:C in Severe Combined Immune Deficient (SCID) Mice

Synthetic TLR4-active Glycolipids as Vaccine Adjuvants and Stand-alone Immunotherapeutics

Contact Info

Product

Resources

About