The proposed research program aims to develop antiinfective agents that act on new or emerging targets, which recognize or process carbohydrate domains in their mechanism of action. The continuing emergence of drug-resistant strains of both bacteria and viruses warrants not only the development of new agents based on established molecular targets, but more importantly the investigation of new targets that have not yet been exploited for drug development. The proposal describes three main areas of research. The first is targeting the bacterial transglycosylase, one of the enzymatic functionalities involved in the assembly of the cell wall peptidoglycan. While the transpeptidase has long been established as the target of p-lactam antibiotics, the transglycosylase remains poorly understood, largely because of the difficulty of accessing its Lipid II substrate, and the lack of a high throughput assay. We will use our experience in expressing this enzyme, and our synthetic experience with Lipid II and related analogues, to develop a high-throughput assay and study in detail the structural determinants of the transglycosylation reaction. Results of this work will be used to design libraries of potential inhibitors, taking advantage of our recent developments in microtiter-based chemistry an in situ screening to rapidly access inhibitors. The second area is targeting the influenza virus neuraminidase and hemagglutinin. We will use our methodology for synthesis of fluoroglycosides to develop bifunctional inhibitors that target both viral proteins. With our collaborator, Ian Wilson, we will focus on the carbohydrate specificity of HA from virulent new avian flu strains. The third area will target CD1d for activation of NKT cells, which is a promising new approach to intervention in both bacterial and viral infections. With our collaborators Ian Wilson and Moriya Tsuji, we have begun to understand the structural basis for selective activation of adjuvant or immunosuppressive responses by glycosylceramide ligands. Using our synthetic methodology, we and our collaborators will continue to develop improved CD1d agonists and define the potential these compounds have in treating bacterial and viral infections. Antibiotic-resistant infections and emerging viruses such as the avian flu pose a significant worldwide threat.
Our research aims to discover new ways to combat these infections, and will result in effective new treatments to cure and prevent them in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI072155-03
Application #
7669431
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Krafft, Amy
Project Start
2007-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$464,749
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wang, Xiaolei; Krasnova, Larissa; Wu, Kevin Binchia et al. (2018) Towards new antibiotics targeting bacterial transglycosylase: Synthesis of a Lipid II analog as stable transition-state mimic inhibitor. Bioorg Med Chem Lett 28:2708-2712
Zhou, Tongqing; Zheng, Anqi; Baxa, Ulrich et al. (2018) A Neutralizing Antibody Recognizing Primarily N-Linked Glycan Targets the Silent Face of the HIV Envelope. Immunity 48:500-513.e6
Dey, Supriya; Wong, Chi-Huey (2018) Programmable one-pot synthesis of heparin pentasaccharides enabling access to regiodefined sulfate derivatives. Chem Sci 9:6685-6691
Shivatare, Sachin S; Chang, Shih-Huang; Tsai, Tsung-I et al. (2016) Modular synthesis of N-glycans and arrays for the hetero-ligand binding analysis of HIV antibodies. Nat Chem 8:338-46
Hsu, Che-Hsiung; Park, Sangho; Mortenson, David E et al. (2016) The Dependence of Carbohydrate-Aromatic Interaction Strengths on the Structure of the Carbohydrate. J Am Chem Soc 138:7636-48
Hsu, Che-Hsiung; Schelwies, Mathias; Enck, Sebastian et al. (2014) Iminosugar C-glycoside analogues of ?-D-GlcNAc-1-phosphate: synthesis and bacterial transglycosylase inhibition. J Org Chem 79:8629-37
Chen, Wentao; Enck, Sebastian; Price, Joshua L et al. (2013) Structural and energetic basis of carbohydrate-aromatic packing interactions in proteins. J Am Chem Soc 135:9877-84
Doores, Katie J; Huber, Michael; Le, Khoa M et al. (2013) 2G12-expressing B cell lines may aid in HIV carbohydrate vaccine design strategies. J Virol 87:2234-41
Al-Shareffi, Esam; Chaubard, Jean-Luc; Leonhard-Melief, Christina et al. (2013) 6-alkynyl fucose is a bioorthogonal analog for O-fucosylation of epidermal growth factor-like repeats and thrombospondin type-1 repeats by protein O-fucosyltransferases 1 and 2. Glycobiology 23:188-98
Lenger, Janina; Schroder, Marius; Ennemann, Eva C et al. (2012) Evaluation of sulfatase-directed quinone methide traps for proteomics. Bioorg Med Chem 20:622-7

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