title: Bioactivity screening of partially desulfated low-molecular-weight heparins: a structure/activity relationship study.
abstract: A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1α), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates.
authors.affiliation: Momenta Pharmaceuticals, Cambridge, MA 02142, USA.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Roy
authors.forename: Hsuanchi
authors.initials: H
authors.lastname: Lai
authors.forename: Radouane
authors.initials: R
authors.lastname: Zouaoui
authors.forename: Jay
authors.initials: J
authors.lastname: Duffner
authors.forename: He
authors.initials: H
authors.lastname: Zhou
authors.forename: Lakshmi
authors.initials: L
authors.lastname: P Jayaraman
authors.forename: Ganlin
authors.initials: G
authors.lastname: Zhao
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Ganguly
authors.forename: Takashi K
authors.initials: TK
authors.lastname: Kishimoto
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkataraman
mesh_terms: D000818:Animals; D001665:Binding Sites; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006868:Hydrolysis; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D019007:P-Selectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism; D020349:Surface Plasmon Resonance; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D006495:Heparin, Low-Molecular-Weight; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D054852:Small Molecule Libraries; D013431:Sulfates; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2