Polyacrylamides Bearing Pendant .alpha.-Sialoside Groups Strongly Inhibit Agglutination of Erythrocytes by Influenza A Virus: Multivalency and Steric Stabilization of Particulate Biological Systems

Lees, Watson J.; Spaltenstein, Andrew; Kingery-Wood, Jill; Whitesides, George M.

doi:10.1021/jm00046a027

Cited by 195 publications

(195 citation statements)

References 22 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…We attribute the enhanced toxicity attenuation properties of the sialic acid containing polymers to the increased sialic acid valency in these materials. There are many examples of the role of valency in adhesion of ligands to multivalent materials [48][49][50][51][52][53]. More specific to Aβ, others have shown for biological membranes that Aβ binding affinity to sialic acid containing gangliosides increased in clustered or multivalent regions of the membrane compared to membrane regions where sialic acids or gangliosides were unclustered [25,30].…”

Section: Discussionmentioning

confidence: 99%

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

2008

View full text Add to dashboard Cite

Abstractβ-Amyloid peptide (Aβ), the primary protein component in senile plaques associated with Alzheimer's disease (AD), has been implicated in neurotoxicity associated with AD. Previous studies have shown that the Aβ-neuronal membrane interaction plays a crucial role in Aβ toxicity. More specifically, it is thought that Aβ interacts with ganglioside rich and sialic acid rich regions of cell surfaces. In light of such evidence, we have hypothesized that the Aβ-membrane sialic acid interaction could be inhibited through use of a biomimic multivalent sialic acid compound that would compete with the cell surface for Aβ binding. To explore this hypothesis, we synthesized a series of photocrosslinked sialic acid containing oligosaccharides and tested their ability to bind Aβ and attenuate Aβ toxicity in cell culture assays. We show that a polymer prepared via the photocrosslinking of disialyllacto-N-tetraose (DSLNT) was able to attenuate Aβ toxicity at low micromolar concentrations without adversely affecting the cell viability. Polymers prepared from mono-sialyl-oligosaccharides were less effective at Aβ toxicity attenuation. These results demonstrate the feasibility of using photocrosslinked sialyl-oligosaccharides for prevention of Aβ toxicity in vitro and may provide insight into the design of new materials for use in attenuation of Aβ toxicity associated with AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

2008

View full text Add to dashboard Cite

show abstract

“…77 Many multivalent inhibitors, including neoglycopolymers, have been synthesized for biological applications. 78,79 Dendrimers are attractive scaffolds for constructing multivalent ligands because of their globular shape and the high local density of ligand presentation on the surface. 80 -82 By applying our chain-walking methodology, we found that the simple copolymerization of ethylene with a mannose-containing comonomer (13) at a low value of P E and a low comonomer concentration resulted in a mannose-coated dendritic copolymer.…”

Section: Chain Walking: a New Strategy For Controlling Polymer Topologymentioning

confidence: 99%

Z. Guan, Control of polymer topology through late‐transition‐metal catalysis, J Polym Sci Part A: Polym Chem (2003), 41(22), 3680–3692

Guan

2003

J. Polym. Sci. A Polym. Chem.

View full text Add to dashboard Cite

ABSTRACT:In this article, recent examples are reviewed of late-transition-metal catalysis applied to polymer topology control. By the judicious selection or design of latetransition-metal catalysts, polymers with a broad range of topologies, including linear, short-chain-branched, hyperbranched, dendritic, and cyclic topologies, have been successfully synthesized. A distinctive advantage of the catalyst approach is that polymers with complex topologies can be prepared in one pot from simple commercial monomers. A fundamental difference of the catalyst approach with respect to other approaches is that the polymer topology is controlled by the catalysts instead of the monomer structure. In our own laboratory, we have successfully used two strategies to control the polymer topology with late-transition-metal catalysts. In the first strategy, hyperbranched polymers are prepared by the direct free-radical polymerization of divinyl monomers through control of the competition between propagation and chain transfer with a cobalt chain-transfer catalyst. In the second strategy, polyethylene topology is successfully controlled by the regulation of the competition between propagation and chain walking with the Brookhart Pd II -␣-bisimine catalyst.

show abstract

“…In particular, small-molecule inhibitors covalently conjugated to a biocompatible polymer have been reported to inhibit human influenza strains (17) and prevent influenza binding to red blood cells (18,19). We have previously shown that the antiviral efficacy of ZA is dramatically enhanced when multiple copies thereof are attached via a flexible linker to the benign and biodegradable polymer poly-L-glutamine (PGN) (20): the resultant PGN-attached drug (PGN-ZA) is 1,000-to 10,000-fold more potent than monomeric ZA in plaque reduction assays and, importantly, is effective even against ZA-and oseltamivir-resistant influenza viruses.…”

mentioning

confidence: 99%

Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection

Lee

Weight²,

Haldar³

et al. 2012

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

View full text Add to dashboard Cite

Covalently conjugating multiple copies of the drug zanamivir (ZA; the active ingredient in Relenza) via a flexible linker to poly-L-glutamine (PGN) enhances the anti-influenza virus activity by orders of magnitude. In this study, we investigated the mechanisms of this phenomenon. Like ZA itself, the PGN-attached drug (PGN-ZA) binds specifically to viral neuraminidase and inhibits both its enzymatic activity and the release of newly synthesized virions from infected cells. Unlike monomeric ZA, however, PGN-ZA also synergistically inhibits early stages of influenza virus infection, thus contributing to the markedly increased antiviral potency. This inhibition is not caused by a direct virucidal effect, aggregation of viruses, or inhibition of viral attachment to target cells and the subsequent endocytosis; rather, it is a result of interference with intracellular trafficking of the endocytosed viruses and the subsequent virusendosome fusion. These findings both rationalize the great antiinfluenza potency of PGN-ZA and reveal that attaching ZA to a polymeric chain confers a unique mechanism of antiviral action potentially useful for minimizing drug resistance.

show abstract

Polyacrylamides Bearing Pendant .alpha.-Sialoside Groups Strongly Inhibit Agglutination of Erythrocytes by Influenza A Virus: Multivalency and Steric Stabilization of Particulate Biological Systems

Cited by 195 publications

References 22 publications

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

Z. Guan, Control of polymer topology through late‐transition‐metal catalysis, J Polym Sci Part A: Polym Chem (2003), 41(22), 3680–3692

Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection

Contact Info

Product

Resources

About