title: Anti-HIV-1 activity and structure-activity-relationship study of a fucosylated glycosaminoglycan from an echinoderm by targeting the conserved CD4 induced epitope.
abstract: BACKGROUND
  Fucosylated glycosaminoglycan (FG) is a novel glycosaminoglycan with a chondroitin sulfate-like backbone and fucose sulfate branches. The aim of this study is to investigate the mechanism and structure-activity relationships (SAR) of FG for combating HIV-1 infection.
  
  
  METHODS
  Anti-HIV activities of FGs were assessed by a cytopathic effect assay and an HIV-1 p24 detection assay. The biomolecule interactions were explored via biolayer interferometry technology. The SAR was established by comparing its anti-HIV-1 activities, conserved CD4 induced (CD4i) epitope-dependent interactions and anticoagulant activities.
  
  
  RESULTS
  FG efficiently and selectively inhibited the X4- and R5X4-tropic HIV-1 infections in C8166 cells with little cytotoxicity against C8166 cells and PBMCs. Our data indicated that FG bound to gp120 with nanomolar affinity and may interact with CD4i of gp120. Additionally, the CD4i binding affinity of FG was higher than that of dextran sulfate. SAR studies suggested that the unique sulfated fucose branches account for the anti-HIV-1 activity. The molecular size and present carboxyl groups of FG may also play important roles in various activities. Notably, several FG derivatives showed higher anti-HIV-1 activities and much lower anticoagulant activities than those of heparin.
  
  
  CONCLUSIONS
  FG exhibits strong activity against X4- and R5X4-tropic HIV-1 infections. The mechanism may be related to targeting CD4i of gp120, which results in inhibition of HIV-1 entry. The carboxyl group substituted derivatives of FG (8.5-12.8kDa), might display high anti-HIV-1 activity and low anticoagulant activity.
  
  
  CONCLUSIONS
  Our data supports further the investigation of FG derivatives as novel HIV-1 entry inhibitors targeting CD4i.
authors.affiliation: Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Lian
authors.forename: Mingyi
authors.initials: M
authors.lastname: Wu
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.forename: Na
authors.initials: N
authors.lastname: Gao
authors.forename: Chuang
authors.initials: C
authors.lastname: Xiao
authors.forename: Zi
authors.initials: Z
authors.lastname: Li
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yongtang
authors.initials: Y
authors.lastname: Zheng
authors.forename: Wenlie
authors.initials: W
authors.lastname: Peng
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D002460:Cell Line; D004447:Echinodermata / Q000737:chemistry*; D000939:Epitopes / Q000276:immunology*; D005643:Fucose / Q000737:chemistry*; D006025:Glycosaminoglycans / Q000737:chemistry*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008970:Molecular Weight; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D000939:Epitopes; D006025:Glycosaminoglycans; D015699:HIV Envelope Protein gp120; D005643:Fucose
keywords: APTT; AR2G; Amine Reactive Second-Generation; Anti-human immunodeficiency virus activity; BLI; Biolayer interferometry; Cluster of Differentiation 4 induced epitope; Envelope glycoprotein 120; FG; Glycosaminoglycan; HIV-1; Mw; SA; Structure–activity relationship; activated partial thromboplastin time; biolayer interferometry; dFG; depolymerized fucosylated glycosaminoglycan; fucosylated glycosaminoglycan; human immunodeficiency virus type 1; molecular weight; streptavidin biosensors