Generation of “Neoheparin” from E. coli K5 Capsular Polysaccharide

Lindahl, Ulf; Li, Jinping; Kusche-Gullberg, Marion; Salmivirta, Markku; Alaranta, Sakari; Veromaa, Timo; Emeis, J.J.; Roberts, Ian S.; Taylor, Craig; Oreste, Pasqua; Zoppetti, G; Naggi, Annamaria; Torri, Giangiacomo; Casu, Benito

doi:10.1021/jm049812m

Cited by 114 publications

(85 citation statements)

References 18 publications

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“…The backbone of the compounds tested in the present study is the capsular K5 polysaccharide of E. coli, which has the same structure as the biosynthetic precursor of heparin/heparan sulfate, N-acetyl heparosan, on which sulfate groups are inserted in different positions and degrees (25). In the compounds tested in the present study, C5 epimerization was introduced to improve the flexibility of the K5 polysaccharide chain (5,17).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we also obtained and tested N-, O-, and N,O-sulfated K5 epimers (Epi-K5) (25), generated by extractive and/or recombinant C5 epimerase, which converts GlcA residues into iduronic acid (IdoA), in order to improve the flexibility of the K5 polysaccharide chain (5,17). Indeed, these K5 derivatives are here shown to possess anti-HSV-1 and anti-HSV-2 activities that, combined with the activity against HIV-1, make them suitable for future development as candidate microbicides to prevent the sexual transmission of different enveloped viruses.…”

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confidence: 99%

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Inhibition of Herpes Simplex Virus Types 1 and 2 In Vitro Infection by Sulfated Derivatives of Escherichia coli K5 Polysaccharide

Pinna

Oreste²,

Coradin

et al. 2008

Antimicrob Agents Chemother

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Herpes simplex virus type 1 (HSV-1) and HSV-2 are neurotropic viruses and common human pathogens causing major public health problems such as genital herpes, a sexually transmitted disease also correlated with increased transmission and replication of human immunodeficiency virus type 1 (HIV-1). Therefore, compounds capable of blocking HIV-1, HSV-1, and HSV-2 transmission represent candidate microbicides with a potential added value over that of molecules acting selectively against either infection. We report here that sulfated derivatives of the Escherichia coli K5 polysaccharide, structurally highly similar to heparin and previously shown to inhibit HIV-1 entry and replication in vitro, also exert suppressive activities against both HSV-1 and HSV-2 infections. In particular, the N,O-sulfated [K5-N,OS(H)] and O-sulfated epimerized [Epi-K5-OS(H)] forms inhibited the infection of

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of Herpes Simplex Virus Types 1 and 2 In Vitro Infection by Sulfated Derivatives of Escherichia coli K5 Polysaccharide

Pinna

Oreste²,

Coradin

et al. 2008

Antimicrob Agents Chemother

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“…While this approach demonstrated for the first time the feasibility of enzymatic synthesis of HS, only microgram amounts of product were generated, making extensive biological studies impossible. Recently, Lindahl and colleagues reported an alternative chemoenzymatic approach for the synthesis of anticoagulant heparin from heparosan, an E. coli K5 capsular polysaccharide (54). This method utilized the C 5 epimerase to convert D-glucuronic acid (GlcUA) to L-iduronic acid (IdoUA), followed by the chemical persulfonation and finally selective desulfonation.…”

Section: Chemoenzymatic Synthesis Of Hs With Biological Activitiesmentioning

confidence: 99%

Anticoagulant heparan sulfate: structural specificity and biosynthesis

Liu

Pedersen

2007

Appl Microbiol Biotechnol

122

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SummaryHeparan sulfate (HS) is present on the surface of endothelial and surrounding tissues in large quantities. It plays important roles in regulating numerous functions of the blood vessel wall, including blood coagulation, inflammation response and cell differentiation. HS is a highly sulfated polysaccharide containing glucosamine and glucuronic/iduronic acid repeating disaccharide units. The unique sulfated saccharide sequences of HS determine its specific functions. Heparin, an analogue of heparan sulfate, is the most commonly used anticoagulant drug. Because of its wide range of biological functions, HS has become an interesting molecule to biochemists, medicinal chemists and developmental biologists. Here, we summarize recent progress towards understanding the interaction between heparan sulfate and blood coagulating factors, the biosynthesis of anticoagulant heparan sulfate and the mechanism of action of heparan sulfate biosynthetic enzymes. Further, knowledge of the biosynthesis of HS facilitates the development of novel enzymatic approaches to synthesize HS from bacterial capsular polysaccharides and to produce polysaccharide end products with high specificity for the biological target. These advancements provide the foundation for the development of polysaccharide-based therapeutic agents.

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“…4,5 The in vitro chemoenzymatic synthesis of anticoagulant heparin-like polysaccharide from heparosan has shown promise as an alternative approach to produce heparin from non-animal source. [6][7][8][9] Therefore, the production of heparosan is the first step in making bioengineered heparin. 10 Heparosan is biosynthesized as a polysaccharide capsule in bacteria including Escherichia coli K5 and Pasteurella multicida.…”

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confidence: 99%