Development of a fundamental technology, which is applicable to drug development and therapeutic applications through analysis of sulfated glycosaminoglycan chains

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(1)It has been demonstrated that congenital human spondyloepiphysial dysplasia is caused by a mutation of the chondroitin 6-O-sulfotransferase 1 gene.(2)The nematode ortholog PAR2.4 of the human chondroitin polymerizing factor (ChPF) that is involved in the biosynthesis of chondroitin has been cloned. Furthermore it was found that downregulation of PAR2.4 by RNAi resulted in the cytokinesis defect during embryonic development of the nematode, which resembled the defect caused by RNAi of chondroitin synthase, indicating the essential role of PAR2.4 in the synthesis of chondroitin as well as the critical role of chondroitin in cytokinesis.(3)Various biological activities have been demonstrated for CS/DS hybrid chains isolated from shark skin, suggesting a possible therapeutic applications of the CS/DS chains.(4)It has been proved that the neurite outgrowth promoting activity of CS/DS chains from embryonic mouse brains is exhibited by molecular interactions with a growth factor pleiotrophin. Sulfated decasaccharides derived from the functional domains have also been isolated and sequenced.(5)A monoclonal antibody specific for dermatan sulfate was developed using an oversulfated dermatan sulfate preparation with a potent neurite outgrowth promoting activity, which was purified from marine ascidian. The antibody apecifically bound to mouse hippocampal neurons, and inhibited the neurite outgrowth promoting activity, which was exhibited by the DS preparation used as an immunogen.(6)Conventionally herpes simplex virus (HSV-1 and HSV-2) have been considered to infect cells through attachment to heparan sulfate chains on cell surface. In this study it has been demonstrated the infection is more strongly inhibited by CS-E than heparin. Furthermore the CS-E structure has beendemonstrated on cell surface. There results suggest that the viruses use CS-E more efficiently than heparan sulfate for their infection.