Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 137, Issue 16, Pages 5248-5251Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja511237n
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Funding
- Alberta Glycomics Centre
- Canada Foundation for Innovation (CFI)
- National Institutes of Health [R01 GM094919, P41 GM103390]
- Science Foundation of Ireland [08/IN.1/B2070]
- Alberta Innovates
- U.S. Department of Energy (DOE), Office of Biological and Environmental Research (OBER) [DE-AC02-06CH11357]
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We describe an approach to accelerate the search for competitive inhibitors for carbohydrate-recognition domains (CRDs). Genetically encoded fragment-based-discovery (GE-FBD) uses selection of phagedisplayed glycopeptides to dock a glycan fragment at the CRD and guide selection of Synergistic peptide motifs adjacent to the CRD. Starting from concanavalin A (ConA), a mannose (Man)-binding protein, as a bait, we narrowed a library of 10(8) glycopeptides to 86 leads that share a consensus motif, Man-WYD. Validation of synthetic leads yielded Man-WYDLF that exhibited 40 50-fold enhancement in affinity over methyl alpha-D-mannopyranoside (MeMan). Lectin array Suggested specificity: Man-WYD derivative bound only to 3 out of 17 proteins-ConA, LcH, and PSA-that bind to Man. An X-ray structure of ConA.:Man-WYD proved that the trimannoside core and Man-WYD exhibit identical CRD docking; but their extra-CRD binding modes are significantly. different. Still, they have comparable affinity and selectivity for various Man-binding proteins. The intriguing observation provides new insight into functional mimicry :of carbohydrates by peptide ligands. GE-FBD may provide an alternative to rapidly search for competitive inhibitors for lectins.
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