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Title: Genetically Encoded Fragment-Based Discovery of Glycopeptide Ligands for Carbohydrate-Binding Proteins

Journal Article · · Journal of the American Chemical Society
DOI:https://doi.org/10.1021/ja511237n· OSTI ID:1261431
 [1];  [1];  [1];  [1];  [2];  [1];  [3];  [4];  [5];  [6];  [6];  [1];  [5];  [3];  [7];  [2];  [1]
  1. Univ. of Alberta, Edmonton, AB (Canada)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Biology and Soft Matter Division
  3. New York Univ. (NYU), NY (United States). Biomedical Chemistry Inst.
  4. Univ. of Georgia, Athens, GA (United States)
  5. New England Biolabs, Ipswich, MA (United States)
  6. Univ. of Calgary, AB (Canada)
  7. National Univ. of Ireland, Galway (Ireland)
+ Show Author Affiliations

Here 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 108 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 α-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.

Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER); Canada Foundation for Innovation (CFI); National Institutes of Health (NIH)
Grant/Contract Number:
AC05-00OR22725; AC02- 06CH11357; R01 GM094919; P41 GM103390; 08/IN.1/B2070
OSTI ID:
1261431
Journal Information:
Journal of the American Chemical Society, Vol. 137, Issue 16; ISSN 0002-7863
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 52 works
Citation information provided by
Web of Science

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Cited By (12)

High‐Throughput Approaches in Carbohydrate‐Active Enzymology: Glycosidase and Glycosyl Transferase Inhibitors, Evolution, and Discovery journal July 2019
Selection of galectin-3 ligands derived from genetically encoded glycopeptide libraries journal September 2018
Multivalent Peptide-Nanoparticle Conjugates for Influenza-Virus Inhibition journal April 2017
Sugared biomaterial binding lectins: achievements and perspectives journal January 2016
High‐Throughput Approaches in Carbohydrate‐Active Enzymology: Glycosidase and Glycosyl Transferase Inhibitors, Evolution, and Discovery journal July 2019
Compositional Bias in Naïve and Chemically-modified Phage-Displayed Libraries uncovered by Paired-end Deep Sequencing journal January 2018
Glycans in drug discovery journal January 2019
Rapid biocompatible macrocyclization of peptides with decafluoro-diphenylsulfone journal January 2016
Chemically Modifying Viruses for Diverse Applications journal March 2016
Correction: Rapid biocompatible macrocyclization of peptides with decafluoro-diphenylsulfone journal January 2017
Mammalian lectin arrays for screening host–microbe interactions journal April 2020
SAROTUP: a suite of tools for finding potential target-unrelated peptides from phage display data journal January 2019

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