Elsevier

Carbohydrate Polymers

Volume 83, Issue 2, 10 January 2011, Pages 737-742
Carbohydrate Polymers

Preparation and antiherpetic activities of chemically modified polysaccharides from Polygonatum cyrtonema Hua

https://doi.org/10.1016/j.carbpol.2010.08.044Get rights and content

Abstract

The chemically modified polysaccharides, including sulfated, phosphorylated, carboxymethylated, acetylated and sulfonylated derivatives, were prepared from a neutral polysaccharide (PD) extracted from Polygonatum cyrtonema Hua. These compounds were characterized by FT-IR, 1H NMR and 13C NMR spectroscopy. Antiherpetic activities of natural and modified P. cyrtonema polysaccharide against herpes simplex virus (HSV) induced by cyclophosphamide (CP) were then evaluated on vero cells using cytopathic effect (CPE) inhibition assay. The phorphorylated derivative (P-PD) and sulfated derivative (S-PD), exhibited significant inhibitory activity against HSV in comparison with the native ones, especially, P-PD presented better antiviral potency. In addition, the sulfonylated derivative (Ts-PD) was found to be as effective as PD, and the acetylated derivative (Ac-PD) to be slightly less antiviral effective, whereas carboxymethylated derivative (C-PD) was shown to be almost inactive. The results indicated that the types of function groups appeared to be very important for the antiherpetic activity of polysaccharides.

Introduction

Polysaccharides are known to present a broad range of biological activities comprising antiviral and antitumor action, variable effects on the immune system and anticoagulant activity (Bohn and BeMiller, 1995, Hardena et al., 2009, Kennedy, 1989, Kennedy and White, 1983). In particular, the antiviral effect of polysaccharides against the herpes simplex virus (HSV) has been reported (Arad et al., 2006, Damonte et al., 2004, Karmakar et al., 2010, Luescher-Mattli, 2003, Pujol et al., 2007) and some of these polysaccharides are currently undergoing either preclinical or clinical evaluation (Kleymann, 2005, McReynolds and Garvey-Hague, 2007). Unlike the widely used acyclovir (ACV)-related nucleoside analogues, which all targeted against viral DNA synthesis, polysaccharides interfere with the attachment of virus to host cell surface by binding to viral envelope glycoprotein (Damonte et al., 2004, Duarte et al., 2001, Neyts et al., 1992, Witvrouw and De Clercq, 1997). In contrast with ACV, which may result in some undesirable complications (Richman et al., 1987) and also induce the emergence of drug-resistant viruses (Coen, 1991, Larder et al., 1989) after prolonged treatment in immunocompromised patients, polysaccharides have the relatively low mammalian toxicity and the novel antiviral mechanism. Thus, the development of the potential of polysaccharides as anti-HSV agents will be of considerable interest.

Polygonatum cyrtonema Hua, a species of the Liliaceae family, is a widely used traditional Chinese medicine for the treatment of cough, dizziness and lung problems. The neutral polysaccharide (PD) isolated from P. cyrtonema Hua has been reported to show immunomodulatory, anti-aging and antiviral activities (Gu et al., 2003, Shi et al., 1999), and has been implicated to be the major bioactive component of the herb. The structure of PD is a branched fructan core with (2→6)-linked β-d-fructofuranosyl (Fruf) residues every three (2→1)-linked β-d-Fruf residues and an average degree of polymerization (DP) of 28 (Liu, Liu, Meng, Yan, & He, 2004). Compared to other antiherpetic polysaccharides, such as sulfated polysaccharides, PD possesses a low molecular weight and no ionic groups. A structure activity relationship (SAR) of polysaccharide has been proposed, which suggests that the antiviral activity of polysaccharide is strongly dependent on the presence of suitable ionic groups with appropriate degree of substitution (DS) (Bohn and BeMiller, 1995, Kulicke et al., 1997). Moreover, some reports revealed that the polysaccharide linked to anionic features of the molecules showed more potent antiherpetic activity than the neutral ones (Baba et al., 1988, Talarico et al., 2004). To our knowledge, neither the introduction of ionic groups to the PD, nor the antiviral activity of their chemically modified derivatives has been reported. Evidently, modifying the structure of PD is favorable and necessary to provide an opportunity to obtain new pharmacological agents with possible therapeutic uses. Herein we prepared a series of chemically modified polysaccharides, including sulfated, phosphorylated, carboxymethylated, acetylated and sulfonylated derivatives (Chart 1). The comparison of their in vitro antiherpetic activities was also reported for the first time.

Section snippets

Materials

The rhizome of P. cyrtonema Hua was collected from Yibin city, Sichuan Province, China, in autumn and authenticated by Professor Zuocheng Zhao at Chengdu Institute of Biology, Chinese Academy of Sciences. PD was isolated from 85% ethanol soluble extracts of the rhizome of P. cyrtonema Hua according to the method previously reported (Liu et al., 2004), using multistep anion exchange and size exclusion chromatography. Bio Gel P2, P4 were purchased from Bio-rad Laboratories, USA. RPMI-1640,

Preparation and characterization of PD derivatives

Starting from a neutral polysaccharide (PD) extracted from P. cyrtonema Hua, five chemically modified derivatives of PD were readily synthesized as a mixture with different substituted positions purified by a Bio Gel P4 column according to the method described in the literature (Tao et al., 2009, Vogl et al., 2000, Xu et al., 2009). Their yields, degrees of substitution and optical rotations were given in Table 1. Relatively to PD, the weights of sulfated (S-PD), carboxymethylated (C-PD), and

Conclusion

The chemical modification of polysaccharides from P. cyrtonema Hua was carried out in the present paper. The successful synthesis of the chemically modified polysaccharide was verified either by IR analysis or by NMR spectroscopy. We found that the phosphorylated and sulfated derivatives of the P. cyrtonema polysaccharides exhibited higher inhibitory activity against HSV-2 than that of the native material. Compared to S-PD, P-PD seemed to be a better inhibitor. Given the interesting chemical

Acknowledgements

We are grateful for the financial supports from the National Science Foundation of China (20972153) and from the Knowledge Innovation Program of the Chinese Academy of Sciences (CIB-2007-LYQY-06).

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