Synthesis and biological evaluation of novel lipid A antagonists

Peri, Francesco; Marinzi, Chiara; Baráth, Marek; Granucci, Francesca; Urbano, Matteo; Nicotra, Francesco

doi:10.1016/j.bmc.2005.08.047

Cited by 24 publications

(22 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These antagonists include naturally occurring lipid A precursors, 10 as well as a number of synthetic analogs of these precursors. 11,12 The most widely studied analog is a synthetic analog based on the lipid A of Rhodobacter sphaeroides or R. capsulatus, two species having very similar lipid A structures. [13][14][15][16] Although the lipid As of R. sphaeroides/R.…”

Section: Introductionmentioning

confidence: 99%

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

2007

View full text Add to dashboard Cite

LPS from Rhizobium sin-1 (R. sin-1) can antagonize the production of tumor necrosis factor alpha (TNF-α) by E. coli LPS in human monocytic cells. Therefore these compounds provide interesting leads for the development of therapeutics for the prevention or treatment of septic shock. Detailed structure activity relationship studies have, however, been hampered by the propensity of these compounds to undergo β-elimination to give biological inactive enone derivatives. To address this problem, we have chemically synthesized in a convergent manner a R. sin-1 lipid A derivative in which the β-hydroxy ester at C-3 of the proximal sugar unit has been replaced by an ether linked moiety. As expected, this derivative exhibited a much-improved chemical stability. Furthermore, its ability to antagonize TNF-α production induced by enteric LPS was only slightly smaller than that of the parent ester modified derivative demonstrating that the ether-linked lipids affect biological activities only marginally. Furthermore, it has been shown for the first time that R. sin-1 LPS and the ether modified lipid A are also able to antagonize the production of the cytokine interferoninducible protein 10, which arises from the TRIF-dependent pathway. The latter pathway was somewhat more potently inhibited than the MyD88-dependent pathway. Furthermore, it was observed that the natural LPS possesses much greater activity than the synthetic and isolated lipid As, which indicates that di-KDO moiety is important for optimal biological activity. It has also been found that isolated R. sin-1 LPS and lipid A agonize a mouse macrophage cell line to induce the production of TNF-α and interferon beta in a Toll-like receptor 4-dependent manner demonstrating species specific properties.

show abstract

Section: Introductionmentioning

confidence: 99%

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

2007

View full text Add to dashboard Cite

show abstract

“…20) [85]. In attempts to mimic the putative intermediate formed in N-acetylglucosaminidase-catalyzed glycoside hydrolysis, imidazolines such as 49 proved to be potent (K i ~ 0.087 M) and selective inhibitors of family 20 N-acetylglucosaminidases [86].…”

Section: Miscellaneous Pyranose N-glycosidesmentioning

confidence: 99%

Pyranose N-Glycosyl Amines: Emerging Targets With Diverse Biological Potential

Norris¹

2008

CTMC

View full text Add to dashboard Cite

Interest in the chemistry and biological properties of non-nucleoside N-glycosidic compounds has gathered pace over the past several years; the occurrence of the N-glycoside moiety in glycoproteins and a range of active natural products has prompted the synthesis of a diverse spectrum of related materials with promising potential in medicinal chemistry. Particularly prominent has been the synthesis of novel N-glycosyl amides, 1,2,3-triazoles, and progress in the construction and diversification of natural products such as the mannopeptimycins and indolocarbazoles, each of which are discussed in this article.

show abstract

“…Peri and coworkers 165 developed synthetic Lipid A derivatives that, on the other hand, largely depart from natural Lipid A structural motifs. Thus, compound 24 (Fig.…”

Section: Modulation Of the Lps Receptor Complex By Lipid A Analoguesmentioning

confidence: 99%

“…Following the lead of compound 43 , 170 as well as their previous work with nonphosphorylated N(OMe)-linked disaccharides, 165 Peri, Nicotra, and coworkers synthesized monosaccharide Lipid A analogues that featured no phosphate groups, a glucose backbone, and an amine ( 46 ), ammonium species ( 47 ), and hydroxylamine ( 48 ) moiety (Fig. 11).…”

Section: Modulation Of the Lps Receptor Complex By Lipid A Analoguesmentioning

confidence: 99%

Modulating LPS Signal Transduction at the LPS Receptor Complex with Synthetic Lipid A Analogues

White

Demchenko

2014

Advances in Carbohydrate Chemistry and Biochemistry

View full text Add to dashboard Cite

Sepsis, defined as a clinical syndrome brought about by an amplified and dysregulated inflammatory response to infections, is one of the leading causes of death worldwide. Despite persistent attempts to develop treatment strategies to manage sepsis in the clinical setting, the basic elements of treatment have not changed since the 1960s. As such, the development of effective therapies for reducing inflammatory reactions and end-organ dysfunction in critically ill patients with sepsis remains a global priority. Advances in understanding of the immune response to sepsis provide the opportunity to develop more effective pharmaceuticals. This article details current information on the modulation of the lipopolysaccharide (LPS) receptor complex with synthetic Lipid A mimetics. As the initial and most critical event in sepsis pathophysiology, the LPS receptor provides an attractive target for antisepsis agents. One of the well-studied approaches to sepsis therapy involves the use of derivatives of Lipid A, the membrane-anchor portion of an LPS, which is largely responsible for its endotoxic activity. This article describes the structural and conformational requirements influencing the ability of Lipid A analogues to compete with LPS for binding to the LPS receptor complex and to inhibit the induction of the signal transduction pathway by impairing LPS-initiated receptor dimerization.

show abstract

Synthesis and biological evaluation of novel lipid A antagonists

Cited by 24 publications

References 27 publications

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Agonistic and antagonistic properties of a Rhizobium sin-1 lipid A modified by an ether-linked lipid

Pyranose N-Glycosyl Amines: Emerging Targets With Diverse Biological Potential

Modulating LPS Signal Transduction at the LPS Receptor Complex with Synthetic Lipid A Analogues

Contact Info

Product

Resources

About