Infectious disease caused by bacterial and viral pathogens pose important challenges in prevention, protection and therapy. Microbial carbohydrates co-evolved with the carbohydrates of their mammalian hosts and provide camouflage to pathogens, a means of interacting with their hosts and utilize a relatively static structure. While microbial carbohydrates offer a potential therapeutic target, their similarity to human carbohydrates require innovative methods for their selective application. The most common approaches to counter infectious disease rely on immunization, protection from infection, and post-infection therapy. Catabolically stable carbohydrates, important yet under exploited targets in controlling infectious disease, are the focus of this proposal. Sialic acid is a common ulosonic acid found at the non-reducing terminus of glycans in the glycocalyx, a carbohydrate shell surrounding animal cells, and in mucins, a highly charged glycoprotein barrier that protects certain tissues. Since glycoconjugates are both remodeled and catabolized from the non-reducing terminus by stepwise enzymatic removal of their saccharide units, the modification of their ulosonic acid component represents a target for blocking such transformation. The possible applications of stable ulosonic acid C-glycosides include: active and passive vaccines, the preparation of nanomaterials or coatings to target or provide a pathogen barrier, and as inhibitors of neuraminidases and hemagglutinins. This proposal describes the design, synthesis and preliminary evaluation of libraries of glycoconjugates containing ulosonic acid C-glycosides for use against pathogens. These molecules will also have impact on biomaterial applications.
The specific aims are the preparation and evaluation of three target libraries: 1. alpha-2,8 C-linked sialic acid oligomers for use in the preparation of meningococcal vaccines; 2. mucin C-linked analogs as anti-infectives/barriers against type 2&3 pathogens and influenza; and 3.sialic acid C-glycosides as neuraminidase/hemagglutinin inhibitors & antiviral agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065786-02
Application #
7336367
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Khambaty, Farukh M
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
2
Fiscal Year
2008
Total Cost
$384,618
Indirect Cost
Name
Rensselaer Polytechnic Institute
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
Zheng, Yingying; Miao, Jianjun; Zhang, Fuming et al. (2016) Surface modification of a polyethylene film for anticoagulant and anti-microbial catheter. React Funct Polym 100:142-150
Suflita, Matthew; Fu, Li; He, Wenqin et al. (2015) Heparin and related polysaccharides: synthesis using recombinant enzymes and metabolic engineering. Appl Microbiol Biotechnol 99:7465-79
Vongchan, Preeyanat; Wutti-In, Yupanan; Sajomsang, Warayuth et al. (2011) N,N,N-Trimethyl chitosan nanoparticles for the delivery of monoclonal antibodies against hepatocellular carcinoma cells. Carbohydr Polym 85:215-220
Bera, Smritilekha; Linhardt, Robert J (2011) Design and synthesis of unnatural heparosan and chondroitin building blocks. J Org Chem 76:3181-93
Cai, Chao; Liu, Jun; Du, Yuguo et al. (2010) Stereoselective total synthesis of (-)-cleistenolide. J Org Chem 75:5754-6
Weiwer, Michel; Chen, Chi-Chang; Kemp, Melissa M et al. (2009) Synthesis and Biological Evaluation of Non-Hydrolizable 1,2,3-Triazole Linked Sialic Acid Derivatives as Neuraminidase Inhibitors. European J Org Chem 2009:
Kemp, Melissa M; Kumar, Ashavani; Mousa, Shaymaa et al. (2009) Synthesis of gold and silver nanoparticles stabilized with glycosaminoglycans having distinctive biological activities. Biomacromolecules 10:589-95
Kim, Jin-Hwan; Huang, Fei; Ly, Mellisa et al. (2008) Stereoselective synthesis of a C-linked neuraminic acid disaccharide: potential building block for the synthesis of C-analogues of polysialic acids. J Org Chem 73:9497-500
Yuan, Xuejun; Ress, Dino K; Linhardt, Robert J (2007) Synthesis of nor-C-linked neuraminic acid disaccharide: a versatile precursor of C-analogs of oligosialic acids and gangliosides. J Org Chem 72:3085-8
Du, Yuguo; Liu, Jun; Linhardt, Robert J (2007) Facile synthesis of (+/-)-paeonilide. J Org Chem 72:3952-4

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