Targeting Inflammation

target-figure1-1024x755A variety of cardiovascular and metabolic disorders, as well as responses among the critically ill surgical patient to injury and repair are all modulated by local inflammatory responses. For example, the recruitment of neutrophils, monocytes, and platelets to the arterial wall is considered a critical step in the earliest stages of atherosclerosis, as well as restenosis following angioplasty and vascular bypass. A significant body of evidence also suggests that an inflammatory cascade, which leads to cytokine-mediated stimulation of metalloproteinase expression, is an important contributing factor in aneurysm expansion. Control of inflammation and innate immune responses expand the prospects for improving clinical outcomes in a broad based group of diseases.

Selectin Antagonists

target-figure2-300x203Selectins (L, E- and P) are class of vascular endothelial molecules that play a critical role in the recruitment of leukocytes to inflamed tissue. In this regard, P-Selectin Glycoprotein-1 (PSGL-1) has been identified as the best characterized ligand for P-selectin. PSGL-1 binds to P-selectin through the interaction of core-2 O-glycan expressing Sialyl Lewis x oligosaccharide and the three tyrosine sulfate residues. Some of the challenges associated with the synthesis of PSGL-1 include obtaining the hexasaccharide component with Sialyl Lewis x portion and the synthesis of tyrosine sulfates in the peptide backbone. The presence of sulfotyrosines is critical to the binding of PSGL-1 as it has been demonstrated previously that without sulfotyrosine residues the glycopeptide will lose substantial activity. We are currently investigating chemical ligation approaches to synthesize glycosulfo peptides and respective mimics as anti-inflammatory agents.

Rele SM, Cui W, Hou S, Barr-Zarse G, Tatton D, Gnanou Y, Esko J, Chaikof EL. Dendrimer-like PEO glycopolymers exhibit anti-inflammatory properties. J Am Chem Soc 2005; 127:10132-10133.

Feng XS, Taton D, Chaikof EL, Gnanou Y. Fast access to dendrimer-like poly(ethylene oxide)s through anionic ring-opening polymerization of ethylene oxide and use of nonprotected glycidol as branching agent. Macromolecules 2009; 42: 7292-7298.

Feng X, Chaikof EL, Absalon C, Drummond C, Taton D, Gnanou Y. Dendritic carrier based on PEG: Design and degradation of acid-sensitive dendrimer-like poly(ethylene oxide)s. Macromol Rapid Comm 2011; 32:1722-1728.

Feng X, Pinaud J, Chaikof EL, Taton Y, Gnanou Y. Sequential functionalization of Janus-type dendrimer-like poly(ethylene oxide)s with camptothecin and folic acid. J Polymer Sci Part A-Polym Chem 2011; 49: 2839-2849.

Krishnamurthy VR, Dougherty A, Kamat M, Song X, Cummings RD, Chaikof EL. Synthesis of a Fmoc-threonine bearing core-2 glycan: A building block for PSGL-1 via Fmoc assisted solid phase peptide synthesis. Carbohydrate Research 2010; 345:1541-1547