Multiple and multivalent interactions of novel anti-AIDS drug candidates, sulfated polymannuronate (SPMG)-derived oligosaccharides, with gp120 and their anti-HIV activities.
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.
Liu
Haiying
H
Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao 266003, People's Republic of China.
Geng
Meiyu
M
Xin
Xianliang
X
Li
Fuchuan
F
Zhang
Zhenqing
Z
Li
Jing
J
Ding
Jian
J
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D006678:HIV / Q000187:drug effects* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006603:Hexuronic Acids / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013055:Spectrophotometry, Infrared; D013431:Sulfates / Q000737:chemistry*; D020349:Surface Plasmon Resonance
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D006603:Hexuronic Acids; D013431:Sulfates; C437391:polymannuronic sulfate