Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist

Yamamoto, Hirofumi; Oda, Masataka; Kanno, Marina; Tamashiro, Shota; Tamura, Ikuko; Yoneda, Toshihiko; Yamasaki, Naoto; Domon, Hisanori; Nakano, Mayo; Takahashi, Hironobu; Terao, Yutaka; Kasai, Yusuke; Imagawa, Hiroshi

doi:10.1248/cpb.c15-00828

Cited by 8 publications

(6 citation statements)

References 33 publications

(29 reference statements)

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“…In a recent study, it was shown that the trehalose derivative named Vizantin (6,6 -bis-O-(3-nonyldodecanoyl)α,α -trehalose) displays adjuvant activity based on TLR4 agonism and binding to the TLR4/MD-2 complex. Based on the known biological activity of lipid A and Vizantin, the authors projected a novel bifunctional glycolipid, that combines the structural features of Vizantin (namely, the two branched FA chains 3-nonyldodecanoic acid, 3NDDA) with the glucosamine core of lipid A (compound 4; Figure 1) [45]. Disaccharide 4 potently antagonizes the LPS/TLR4 signaling pathway in a concentration-dependent manner, in human THP-1 cells, with an IC 50 of 3.8 nM.…”

Section: Lipid a Mimetic With Vizantin-like Branched Chainsmentioning

confidence: 99%

Recent Advances on Toll-Like Receptor 4 Modulation: New Therapeutic Perspectives

Zaffaroni

Peri

2018

Future Med. Chem.

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Activation or inhibition of TLR4 by small molecules will provide in the next few years a new generation of therapeutics. TLR4 stimulation (agonism) by high-affinity ligands mimicking lipid A gave vaccine adjuvants with improved specificity and efficacy that have been licensed and entered into the market. TLR4 inhibition (antagonism) prevents cytokine production at a very early stage; this is in principle a more efficient method to block inflammatory diseases compared to cytokines neutralization by antibodies. Advances in TLR4 modulation by drug-like small molecules achieved in the last years are reviewed. Recently discovered TLR4 agonists and antagonists of natural and synthetic origin are presented, and their mechanism of action and structure-activity relationship are discussed.

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Section: Lipid a Mimetic With Vizantin-like Branched Chainsmentioning

confidence: 99%

Recent Advances on Toll-Like Receptor 4 Modulation: New Therapeutic Perspectives

Zaffaroni

Peri

2018

Future Med. Chem.

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“…proinfl amatorios efectores de la respuesta inmune inducida por los gram negativos en la sepsis. Un mecanismo idéntico como antagonista del lipopolisacárido se ha descrito y probado en modelos animales para el quercetín, principal fl avonoide de las plantas y uno de los principales constituyentes de la dieta humana presente en frutas, verduras y bebidas (16)(17)(18)(19).…”

Section: Tipounclassified

Fisiopatología de la sepsis por bacterias gram negativas: bases moleculares

Fandiño

Barrera

2015

rev cuarzo

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ResumenLa sepsis constituye un complejo síndrome en el que a consecuencia de una respuesta anómala del huésped frente a una infección se desencadenan una serie de mecanismos fi siopatológicos celulares y moleculares que se traducirán en el daño multiorgánico del paciente y su respectivas manifestaciones clínicas. Las bacterias gram negativas, gracias al lipopolisacárido (LPS), principal constituyente de su membrana externa son reconocidas por moléculas como la proteína de unión al lipopolisacàrido (LBP) y por complejos de receptores de membrana celular en el huésped que reconocen su estructura antigé-nica como son el TLR4, el CD14 y la MD2, dando lugar, por medio de diferentes vías de señalización mieloide dependiente (MyD88) y mieloide independiente o TRIF, a la activación de una serie de kinasas que fi nalmente a través de vías de señalización intracelular como como NF -kB, generarán cambios transcripcionales que inducirán la producción de citocinas pro infl amatorias, que explican el Síndrome de respuesta infl amatoria sistémica (SIRS) y las antinfl amatorias, que explican el síndrome de repuesta anti infl amatorio compensatorio (CARS), ambos constituyen las fases de la sepsis a través de los cuales pasa el paciente séptico en diferentes momentos del proceso. Todos estos procesos fi siopatológicos moleculares de la sepsis son los que darán como resultado cambios en el endotelio, la microvasculatura, el sistema del complemento, la coagulación y fi nalmente en cada uno de los órganos del paciente las diferentes manifestaciones clínicas que desde scores de valoración del paciente, como el SOFA, permiten identifi car al paciente en sepsis, su pronóstico y directrices acerca del tratamiento. Es así como la comprensión de las bases fi siopatológicas moleculares de las sepsis por gram negativos constituyen hoy en día la base para su defi nición, la comprensión de la clínica y el punto de partida para mejoras terapéuticas en el manejo de la sepsis, traducida en la supervivencia del paciente.

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“…Because septic shock and/or Gram-negative sepsis are fatal in approximately 30-40% of patients, TLR antagonists for LPS have thus far attracted considerable interest as potential treatments for these methods of sepsis. [13][14][15][16] Recently, we have developed vizantin (1), 17,18) 6,6′-bis-O-(3nonyldodecanoyl)-α,α′-trehalose, as a safe immunostimulator on the basis of a structure-activity relationship study with trehalose 6,6′-dicorynomycolate (TDCM) (2) [19][20][21][22][23][24] that was first characterized as a structural component of the outer surface membrane of Corynebacterium diphtheriae (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Development of a Water Soluble Self-assembling Analogue of Vizantin

Nakano,

Sakamoto,

Yamasaki

et al. 2024

CHEMICAL & PHARMACEUTICAL BULLETIN

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Vizantin, 6,6′-bis-O-(3-nonyldodecanoyl)-α,α′-trehalose, has been developed as a safe immunostimulator on the basis of a structure-activity relationship study with trehalose 6,6′-dicorynomycolate. Our recent study indicated that vizantin acts as an effective Toll-like receptor-4 (TLR4) partial agonist to reduce the lethality of an immune shock caused by lipopolysaccharide (LPS). However, because vizantin has low solubility in water, the aqueous solution used in in vivo assay systems settles out in tens of minutes. Here, vizantin was chemically modified in an attempt to facilitate the preparation of an aqueous solution of the drug. This paper describes the concise synthesis of a water-soluble vizantin analogue in which all the hydroxyl groups of the sugar unit were replaced by sulfates. The vizantin derivative displayed micelle-forming ability in water and potent TLR-4 partial agonist activity.

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Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist

Abstract: Gram-negative sepsis and septic shock are serious conditions caused by the release of bacterial endotoxin.

Cited by 8 publications

References 33 publications

Recent Advances on Toll-Like Receptor 4 Modulation: New Therapeutic Perspectives

Recent Advances on Toll-Like Receptor 4 Modulation: New Therapeutic Perspectives

Fisiopatología de la sepsis por bacterias gram negativas: bases moleculares

Development of a Water Soluble Self-assembling Analogue of Vizantin

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