2008;375:437. model of MAG based on known crystal structures of other siglecs suggests that the Thr positions the glycan such that aryl substitution of the 2C3 sialic acid produces a steric clash with the GalNAc, while attaching an aryl substituent to the other sialic acid positions the substituent near a hydrophobic pocket that accounts to the increase in affinity. experiments that show improvement of nerve regeneration by administration of sialidase to destroy sialic acid dependent ligands. 16 Demonstration that sialoside ligands can reverse MAG dependent inhibition of axon outgrowth 17 has suggested the possibility that small molecules of sufficient potency could also promote nerve regeneration studies due to its relatively low (M) potency, and the rapid clearance of small oligosaccharides from the blood. Since 13c exhibits significantly higher potency (Kd=15 nM), and has increased hydrophobicity due to the 9-aryl substituent, it will be of Lodoxamide interest to determine if it has suitable phamacokinetic properties to evaluate its ability to promote axonal outgrowth in animal models of nerve injury. 16 This would provide an important proof of concept for the use of small molecule inhibitors of MAG for treatment of nerve injury. Longer term, however, we Lodoxamide believe that the approach of minimizing the structural complexity of such inhibitors is ultimately the best route to obtaining pharmaceutically acceptable inhibitors. The detailed understanding of the basis for the potent inhibitory potency of 13c may aid in the rational design of such sialoside mimic inhibitors. Supplementary Material 01Click here to view.(1.1M, pdf) Acknowledgments The authors thank Ola Blixt, Tasneem Islam, and Karin Norgard Sumnicht for discussions and preliminary experiments on the nature of O-linked glycans as inhibitors of MAG, and Anna Crie with help in preparation of the manuscript and Figures. These studies were supported by Lodoxamide NIH give GM60928 (JCP), EMBO fellowship (CR) and Swiss National Science Basis (project 200020-120628 (Become). Footnotes Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been approved for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the producing proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary Material may be found on-line. References and notes 1. Blixt O, Collins Become, vehicle den Nieuwenhof IM, Crocker PR, Paulson JC. J Biol Chem. 2003;278:31007. [PubMed] [Google Scholar] 2. IMMT antibody Shin SY, Gathje H, Schwardt O, Gao GP, Ernst B, Kelm S, Meyer B. Chembiochem. 2008;9:2946. [PubMed] [Google Scholar] 3. Mesch S, Lemme K, Koliwer-Brandl H, Strasser DS, Schwardt O, Kelm S, Ernst B. Carbohydr Res. 2010;345:1348. [PubMed] [Google Scholar] 4. Schwardt O, Gathje H, Vedani A, Mesch S, Gao GP, Spreafico M, von Orelli J, Kelm S, Ernst B. J Med Chem. 2009;52:989. [PubMed] [Google Scholar] 5. Kelm S, Brossmer R, Isecke R, Gross HJ, Strenge K, Schauer R. Eur J Biochem. 1998;255:663. [PubMed] Lodoxamide [Google Scholar] 6. Blixt O, Han S, Liao L, Zeng Y, Hoffmann J, Futakawa S, Paulson JC. J Am Chem Soc. 2008;130:6680. [PMC free article] [PubMed] [Google Scholar] 7. Schwardt O, Koliwer-Brandl H, Zimmerli R, Mesch S, Rossato G, Spreafico M, Vedani A, Kelm S, Ernst B. Bioorg Med Chem. 2010;18:7239. [PubMed] [Google Scholar] 8. Crocker PR, Paulson JC, Varki A. Nat Rev Immunol. 2007;7:255. [PubMed] [Google Scholar] 9. Schnaar RL, Lopez PH. J Neurosci Res. 2009;87:3267. Lodoxamide [PMC free article] [PubMed] [Google Scholar] 10. Zorner B, Schwab ME. Ann N.