Polymerized liposomes containing C-glycosides of sialic acid: potent inhibitors of influenza virus in vitro infectivity

Spevak, Wayne; Nagy, Jon O.; Charych, Deborah H.; Schaefer, Michele L.; Gilbert, James H.; Bednarski, Mark D.

doi:10.1021/ja00056a047

Cited by 184 publications

(117 citation statements)

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“…Liposomes are particularly attractive scaffolds for designing polyvalent inhibitors [9,10,[12][13][14][15]; however, the poor colloidal stability of conventional liposomes and their short circulation times in vivo [16,17] are major obstacles limiting their therapeutic use. We describe the design of highly stable and active polyvalent anthrax toxin inhibitors based on liposomes incorporating polyethylene glycol (PEG)-functionalized lipids (PEGylated liposomes).…”

mentioning

confidence: 99%

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Rai¹,

Vance²,

Poon³

et al. 2008

Chemistry A European J

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The design of polyvalent molecules [1][2][3][4][5], consisting of multiple copies of a ligand attached to a suitable scaffold, represents a promising approach for designing potent inhibitors of pathogens and microbial toxins [1,[6][7][8][9][10][11]. Liposomes are particularly attractive scaffolds for designing polyvalent inhibitors [9,10,[12][13][14][15]; however, the poor colloidal stability of conventional liposomes and their short circulation times in vivo [16,17] are major obstacles limiting their therapeutic use. We describe the design of highly stable and active polyvalent anthrax toxin inhibitors based on liposomes incorporating polyethylene glycol (PEG)-functionalized lipids (PEGylated liposomes). Furthermore, drawing from the concept of lipid rafts [15,18,19] -domains that are believed to exist in cellular membranes -we have designed heterogeneous domain-containing PEGylated liposomes that are considerably more active than their homogeneous counterparts (Scheme 1). These raft-mimetic PEGylated polyvalent liposomes are attractive not only for designing inhibitors for toxins and pathogens, but also for the design of efficient targeted drug delivery systems.While liposomes have been investigated extensively for applications in drug delivery, as described above, conventional liposomes are limited in effectiveness because of their low colloidal stability and their rapid uptake by macrophage cells of the immune system, predominantly in the liver and spleen [20]. The ability to enhance the physical stability and extend the circulation lifetime through modification with PEG, achieved by using lipids with PEG attached to their hydrophilic head groups, has proven to be useful in the context of drug delivery [17,[20][21][22]. We first tested whether the use of PEGylated liposomes (Scheme 1b) would enable the design of stable and active polyvalent anthrax lethal toxin (LeTx) inhibitors.To that end, we made liposomes (100 nm diameter) composed of a 19:1 mixture of 1,2-Distearoyl-sn-Glycero-3-Phosphocholine (DSPC) and a pyridyl dithiopropionate derivative of L-α-Distearoyl Phosphatidylethanolamine-N-[Amino(Polyethylene Glycol)2000] (DSPE-PEG2000-PDP). We functionalized these liposomes with an inhibitory peptide HTSTYWWLDGAPC [9,23] (4.7%) that binds to the heptameric cell-binding component of anthrax toxin, [PA 63 ] 7 , thereby blocking the binding of the toxic enzyme lethal factor (LF). Inhibition of the binding of LF to [PA 63 ] 7 prevents the cytosolic delivery of LF, thereby inhibiting cell death. Peptide-functionalized PEGylated liposomes protected RAW264.7 cells from LeTx with a half maximal inhibitory concentration (IC 50 ) of about 35 nM on a per-peptide basis; control PEGylated liposomes functionalized with thioglycerol showed no inhibitory activity (Fig. 1a). Furthermore, as seen in Fig. 1a, the activity of the polyvalent PEGylated liposomes (Scheme 1b) was comparable to that of conventional (non-PEGylated) DSPC-based liposomes (Scheme 1a) with the same peptide density (20 nM), indicating that the use of ...

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mentioning

confidence: 99%

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Rai¹,

Vance²,

Poon³

et al. 2008

Chemistry A European J

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“…These conjugates have been useful for both site-directed drug delivery [22] and for studies of water-monolayer surface interactions [23]. Calixarenes are efficient sodium ionophores and are applied as such in chemical sensors.…”

Section: Calixarenesmentioning

confidence: 99%

From Zeolite to Host-Guest Nanocomposite Materials

Salavati‐Niasari¹,

Mohandes²

2011

Advances in Diverse Industrial Applications of Nanocomposites

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“…Na Figura 13 encontram-se apresentadas as interações importantes entre o sítio ativo da hemaglutinina do vírus influenza e o receptor sialosídeo da molécula hospedeira. Porém, o sítio ativo da hemaglutinina apresenta uma afinidade fraca por sialosídeos monoméricos (com apenas um resíduo de ácido siálico), o que difi- culta o desenvolvimento de sialilmiméticos que atuem de forma eficiente sobre a hemaglutinina [40][41][42] 18 , que foi sintetizada e avaliada quanto à atividade inibitória da hemaglutinina [43][44][45][46] 14). No entanto, há necessidade de estratégias sintéticas mais elaboradas para a obtenção de sialilmiméticos poliméricos 16 .…”

Section: Desenhando Fármacos Antiinfluenzaunclassified

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

Fátima¹,

Baptistella²,

Pilli³

et al. 2005

Quím. Nova

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Recebido em 4/2/04; aceito em 13/7/04; publicado na web em 23/11/04 SIALIC ACIDS -FROM THE COMPREHENSION OF THEIR INVOLVEMENT IN BIOLOGICAL PROCESSES TO ANTIINFLUENZA DRUG DESIGN. Sialic acids are nine-carbon carbohydrates that occur widely in nature and occupy the terminal portions of some glycoproteins and glycolipids of cell membranes. These carbohydrates are closely involved in cell-cell interactions and in processes such as microbial infection, inflammation, etc. Studies on the participation of sialic acids in biological processes have provided comprehension about their role in the infection by the influenza virus, the causal agent of flu. In this article, we present an overview of the importance of sialic acids in the influenza virus infection and how the knowledge of their involvement in this process has allowed the development of selective and efficient drugs against the virus.Keywords: sialic acid; flu and antiinfluenza drugs. INTRODUÇÃONão há vida sem célula. E a exemplo da própria vida, que tanta diversidade apresenta, variam as formas e funções das células. As células são as unidades estruturais e funcionais de todos os organismos e é possível reconhecer, em sua hierarquia estrutural, alguns níveis de complexidade, como aqueles presentes, por exemplo, em uma célula vegetal: o nível 3 onde se incluem complexos supramoleculares (cromossomo, membrana plasmática, parede celular, etc); o nível 2 representado por macromoléculas (DNA, proteínas, celulose, etc) e o nível 1 compreendendo as unidades monoméricas, como nucleotídeos, aminoácidos, carboidratos, etc 1-3 (Figura 1).A membrana plasmática, presente em células de todas as espécies, define a periferia da célula, separando o seu conteúdo da circunvizinhança. Ela serve como uma barreira de permeabilidade, que permite à célula manter uma composição citoplasmática e é composta de grande número de moléculas de lipídios e proteínas que se mantêm juntas principalmente por interações hidrofóbicas, formando uma bicamada lipídica fina, resistente e flexível, em volta da célula 1-3 . Algumas proteínas presentes na membrana celular permitem a passagem de certos íons e moléculas (proteínas transportadoras). Outras proteí-nas exercem o papel de receptores, transmitindo o sinal do exterior para o interior da célula. Há ainda proteínas que funcionam como enzimas, participando de reações que ocorrem em membranas.

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Polymerized liposomes containing C-glycosides of sialic acid: potent inhibitors of influenza virus in vitro infectivity

Cited by 184 publications

References 1 publication

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

Stable and Potent Polyvalent Anthrax Toxin Inhibitors: Raft‐Inspired Domain Formation in Liposomes that Contain PEGylated Lipids

From Zeolite to Host-Guest Nanocomposite Materials

Ácidos siálicos: da compreensão do seu envolvimento em processos biológicos ao desenvolvimento de fármacos contra o agente etiológico da gripe

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