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Glycobiology Advance Access published online on December 22, 2004
Glycobiology, doi:10.1093/glycob/cwi031
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© Oxford University Press 2004; all rights reserved.
Received September 5, 2004
Revised December 14, 2004
Accepted December 15, 2004

Article

Multiple and Multivalent Interactions of Novel Anti-AIDS Drug Candidates, Sulfated Polymannuronate (SPMG)-derived Oligosaccharides, with gp120, and their Anti-HIV Activities

Haiying Liu 1, Meiyu Geng 1*, Xianliang Xin 2, Fuchuan Li 2, Zhenqing Zhang 2, Jing Li 2, Huashi Guan 2, and Jian Ding 3

1 Both authors contributed equally to this work; Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, P.R.C
2 Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, P.R.C
3 Division of Antitumor pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, P. R. China

* To whom correspondence should be addressed.
Meiyu Geng, E-mail: gengmy{at}ouc.edu.cn


  Abstract

Sulfated polymannuronate (SPMG), a novel anti-AIDS drug candidate, combats HIV-1 infection, mainly by binding to gp120 protein with high affinity. To explore the structural basis of this anti-HIV-1 action, size-defined oligosaccharides were prepared by semi-synthesis or separated from native SPMG. In this study, a series of homogeneously sized SPMG fragments are evaluated for their capacity to bind rgp120 using surface plasmon resonance (SPR) analysis. The minimum SPMG fragment size that interacts with rgp120 is a hexasaccharide. Additionally, binding capacity increases with the molecular size of oligosaccharides, with the affinity of large fragments (≥ 15-16 saccharides) approaching that of full-sized SPMG. Competitive inhibition and stoichiometric analyses disclose that SPMG oligos bind to multiple binding sites on gp120. Sugar chains longer than 15-16 saccharide residues (SPMG) display multivalent interactions, with one sugar chain binding to two or three gp120 molecules. Consistent with binding data, a positive correlation exists between the size of SPMG oligosaccharides and their anti-HIV activity. The octasaccharide is established to be the minimal active fragment inhibiting syncytium formation and lowering the P24 core antigen level in HIV-IIIB-infected CEM cells. Alternatively, about 50% anti-HIV activity was observed for 15-16 saccharide, while 19-20 saccharide fragment displayed anti-HIV activity equivalent to native SPMG. The structures of the unique minimum hexasaccharide specifically recognized by gp120 and the minimum octasaccharide combating HIV-IIIB infection were representatively structured as [ManA (2s){beta}1-4 ManA(2s/3s)]n.

Keywords: anti-HIV-IIIB activity / rgp120 / sulfated polymannuronate / SPMG-derived oligosaccharide / surface plasmon resonance.
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