Multiple and multivalent interactions of novel anti-AIDS drug candidates, sulfated polymannuronate (SPMG)-derived oligosaccharides, with gp120 and their anti-HIV activities.

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 (> or = 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)beta1-4 ManA(2s/3s)]n.

• Authors: Haiying Liu, Meiyu Geng, Xianliang Xin, Fuchuan Li, Zhenqing Zhang, Jing Li, Jian Ding
• Journal: Glycobiology (Glycobiology) Vol. 15 Issue 5 Pg. 501-10 (May 2005) ISSN: 0959-6658 [Print] England
• PMID: 15616125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• HIV Envelope Protein gp120
• Hexuronic Acids
• Sulfates
• polymannuronic sulfate

Topics

• Anti-HIV Agents (chemistry, isolation & purification, metabolism, pharmacology)
• Cell Line
• Drug Design
• HIV (drug effects, metabolism)
• HIV Envelope Protein gp120 (metabolism)
• Hexuronic Acids (chemistry, isolation & purification, metabolism, pharmacology)
• Molecular Structure
• Nuclear Magnetic Resonance, Biomolecular
• Spectrophotometry, Infrared
• Sulfates (chemistry)
• Surface Plasmon Resonance