Glycobiology Advance Access originally published online on December 22, 2004
Glycobiology 2005 15(5):501-510; doi:10.1093/glycob/cwi031
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Glycobiology vol. 15 no. 5 © Oxford University Press 2004; all rights reserved.
Multiple and multivalent interactions of novel anti-AIDS drug candidates, sulfated polymannuronate (SPMG)-derived oligosaccharides, with gp120 and their anti-HIV activities
3 Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, People’s Republic of China, and 4 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, People’s Republic of China
1 These authors contributed equally to this work.
2 To whom correspondence should be addressed; e-mail: gengmy{at}ouc.edu.cn; suozhang{at}mail.shcnc.ac.cn
Received on September 5, 2004; revised on December 14, 2004; accepted on December 15, 2004
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 saccharides, whereas a 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)ß1-4 ManA(2s/3s)]n.
Key words: anti-HIV-IIIB activity / rgp120 / SPMG-derived oligosaccharide / sulfated polymannuronate / surface plasmon resonance
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