Total Synthesis of the Glycopeptide Recognition Domain of the P‐Selectin Glycoprotein Ligand 1

Baumann, Katharina; Kowalczyk, Danuta; Kunz, Horst

doi:10.1002/anie.200705762

Cited by 39 publications

(40 citation statements)

References 55 publications

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“…To date, the design of most existing P-selectin inhibitors has focused on mimicking the C2 O-glycan bearing sLe x moiety and in so doing, these approaches have been largely unsuccessful in accounting for the contribution of critical clustered tyrosine sulfates [119, 124, 130, 131, 138, 139]. Further synthetic challenges have included suboptimal selectivity in glycosylation [140], incompatible protecting groups for the synthesis of oligosaccharides [141], and the acid lability of tyrosine sulfates [142, 143], all of which have contributed to low yield of PSGL-1 GSP mimetics.…”

Section: Next Generation Approaches To Target Psgl-1/p-selectin Intermentioning

confidence: 99%

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Patel

Miranda-Nieves

Chen

et al. 2017

Translational Research

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Obesity-induced insulin resistance and metabolic syndrome continue to pose an important public health challenge worldwide as they significantly increase the risk of type 2 diabetes and atherosclerotic cardiovascular disease. Advances in the pathophysiologic understanding of this process has identified that chronic inflammation plays a pivotal role. In this regard, given that both animal models and human studies have demonstrated that the interaction of P-selectin glycoprotein ligand-1 (PSGL-1) with P-selectin are not only critical for normal immune response, but also are upregulated in the setting of metabolic syndrome, PSGL-1/P-selectin interactions provide a novel target for preventing and treating resultant disease. Current approaches of interfering with PSGL-1/P-selectin interactions include targeted antibodies, recombinant immunoglobulins that competitively bind P-selectin, and synthetic molecular therapies. Experimental models as well as clinical trials assessing the role of these modalities in a variety of diseases have continued to contribute to the understanding of PSGL-1/P-selectin interactions and have demonstrated the difficulty in creating clinically relevant therapeutics. Most recently, however, computational simulations have further enhanced our understanding of the structural features of PSGL-1 and related glycomimetics, which are responsible for high affinity selectin interactions. Leveraging these insights for the design of next generation agents has thus led to development of a promising synthetic method for generating PSGL-1 glycosulfopeptide mimetics for the treatment of metabolic syndrome.

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Section: Next Generation Approaches To Target Psgl-1/p-selectin Intermentioning

confidence: 99%

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Patel

Miranda-Nieves

Chen

et al. 2017

Translational Research

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“…Impressively, this linear, cassette-based method has been employed by the Kunz lab in the synthesis of part of the CD62P ligand PSGL-1 that is involved in the inflammatory response and leukocyte recognition. The resulting 18-residue fragment containing an O-linked hexasaccharide was synthesized in sufficient amounts for use in biomedical studies (Baumann et al, 2008). In the synthesis of N-linked glycopeptides, glycosylated asparagine cassettes are most commonly prepared before or after SPPS through the reaction of a protected or deprotected anomeric glycosyl-amine with an aspartate residue (Figure 3B).…”

Section: Glycosylationmentioning

confidence: 99%

Chemical Methods for Encoding and Decoding of Posttranslational Modifications

Chuh

Batt

Pratt

2016

Cell Chemical Biology

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A large array of posttranslational modifications can dramatically change the properties of proteins and influence different aspects of their biological function such as enzymatic activity, binding interactions, and proteostasis. Despite the significant knowledge that has been gained about the function of posttranslational modifications using traditional biological techniques, the analysis of the site-specific effects of a particular modification, the identification of the full compliment of modified proteins in the proteome, and the detection of new types of modifications remains challenging. Over the years, chemical methods have contributed significantly in both of these areas of research. This review highlights several posttranslational modifications where chemistry-based approaches have made significant contributions to our ability to both prepare homogeneously modified proteins and identify and characterize particular modifications in complex biological settings. As the number and chemical diversity of documented posttranslational modifications continues to rise, we believe that chemical strategies will be essential to advance the field in years to come.

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“…This adhesion process involves binding of E-and Pproteins on the endothelium to E-and P-selectin ligands on the surface of leukocytes [72][73][74][75]. The synthesis of the glycopeptide recognition domain of P-selectin glycoprotein ligand-1 (PSGL-1) [77,78] will be illustrated here [79][80][81]. Migrating tumor cells also express sLe x structures to mimic these ligands in order to facilitate attachment to the endothelial cell surface, resulting in tumor metastasis [76].…”

Section: Synthesis Of Glycopeptide Recognition Domain Of P-selectin Gmentioning

confidence: 99%

“…Introduction of a 4,6-O-benzylidene acetal gave the glucosamine acceptor 38. The sLe x fragment was transformed into a donor (45) by removal of TBDPS group using tetra-n-butylammonium fluoride (TBAF), and subsequently it was reacted with trichloroacetonitrile [88] to give 50 (Schemes 10.8a and 10.9a) [79,80]. Regioselective ring opening of the benzylidene acetal gave acceptor 41 [87], which was reacted with a partially O-acetyl protected galactose trichloroacetimidate donor 42 [88,89] to give the Le x fragment 43 in 63% yield.…”

Section: Synthesis Of Glycopeptide Recognition Domain Of P-selectin Gmentioning

confidence: 99%

Advances inN‐ andO‐Glycopeptide Synthesis – A Tool to Study Glycosylation and Develop New Therapeutics

Westerlind

Kunz

2011

Amino Acids, Peptides and Proteins in Organic Chemistry

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Many proteins are co-or post-translationally modified by mono-or oligosaccharides. It has become evident that these glycoproteins play important roles in diverse biochemical processes. The saccharides contribute with physiochemical properties, which include conformational effects on the protein, stability to proteolysis, and lubrication of cells. In addition, the glycans are involved in cell-cell recognition and cell-external agent interactions. These interactions induce biological events, which include cell growth and differentiation, cell proliferation, cell adhesion, binding of pathogens, fertilization, and immune responses [1-6]. The glycans assist in protein folding and transport, and they are involved in pathogenic processes like chronic inflammation [5], viral and bacterial infections [7-10], tumor growth and metastasis [11,12], and autoimmune disorders [13,14]. The variety of events affected by protein glycosylation is not surprising. Carbohydrates are unique in their structural complexity and, in contrast to oligonucleotides and proteins, they can be connected in more than one form: connected via different configural positions of the glycan residue and also via an anomeric aor b-glycosidic linkage. The different modes of connection can lead to long linear or highly branched saccharide structures. By combining different types of glycans like galactose, glucose, N-acetyl galactosamine (GalNAc), N-acetyl glucosamine (GlcNAc), fucose, mannose, sialic acid, and others, an enormous amount of combinations can be formed. Nature only uses a small portion of these possible combinations. The biosyntheses of different oligosaccharides are dependent of glycosyltransferases, which are gene-encoded. Each type of connection and glycan residue needs a specific enzyme, and for practical reasons this restricts the number of combinations. Nature also limits the number of final products that can be made by having common core structures. The saccharides can be linked to the protein backbone via an O-glycosidic bond or via amide bond formation in N-glycoproteins. In the most common type of O-glycoproteins, the mucin type, a GalNAc residue is connected to the protein backbone via an O-glycosidic linkage to serine or threonine [15,16]. The GalNAc residue can be further extended with

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Total Synthesis of the Glycopeptide Recognition Domain of the P‐Selectin Glycoprotein Ligand 1

Cited by 39 publications

References 55 publications

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Chemical Methods for Encoding and Decoding of Posttranslational Modifications

Advances inN‐ andO‐Glycopeptide Synthesis – A Tool to Study Glycosylation and Develop New Therapeutics

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