Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins

Simon Ng, Edith Lin, Pavel I. Kitov, Katrina F. Tjhung, Oksana O. Gerlits, Lu Deng, Brian Kasper, Amika Sood, Beth M. Paschal, Ping Zhang, Chang Chun Ling, John S. Klassen, Christopher J. Noren, Lara Mahal, Robert J. Woods, Leighton Coates, Ratmir Derda

Research output: Contribution to journalArticle

Abstract

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 phage-displayed 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<sup>8</sup> 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.

Original languageEnglish (US)
Pages (from-to)5248-5251
Number of pages4
JournalJournal of the American Chemical Society
Volume137
Issue number16
DOIs
StatePublished - Apr 29 2015

Fingerprint

Glycopeptides
Carbohydrates
Mannose
Ligands
Concanavalin A
Mannose-Binding Lectin
Peptides
Lectins
Docks
Bacteriophages
saccharide-binding proteins
Carrier Proteins
Polysaccharides
Derivatives
Proteins
X rays
Observation
X-Rays

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Ng, S., Lin, E., Kitov, P. I., Tjhung, K. F., Gerlits, O. O., Deng, L., ... Derda, R. (2015). Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins. Journal of the American Chemical Society, 137(16), 5248-5251. https://doi.org/10.1021/ja511237n

Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins. / Ng, Simon; Lin, Edith; Kitov, Pavel I.; Tjhung, Katrina F.; Gerlits, Oksana O.; Deng, Lu; Kasper, Brian; Sood, Amika; Paschal, Beth M.; Zhang, Ping; Ling, Chang Chun; Klassen, John S.; Noren, Christopher J.; Mahal, Lara; Woods, Robert J.; Coates, Leighton; Derda, Ratmir.

In: Journal of the American Chemical Society, Vol. 137, No. 16, 29.04.2015, p. 5248-5251.

Research output: Contribution to journalArticle

Ng, S, Lin, E, Kitov, PI, Tjhung, KF, Gerlits, OO, Deng, L, Kasper, B, Sood, A, Paschal, BM, Zhang, P, Ling, CC, Klassen, JS, Noren, CJ, Mahal, L, Woods, RJ, Coates, L & Derda, R 2015, 'Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins', Journal of the American Chemical Society, vol. 137, no. 16, pp. 5248-5251. https://doi.org/10.1021/ja511237n
Ng, Simon ; Lin, Edith ; Kitov, Pavel I. ; Tjhung, Katrina F. ; Gerlits, Oksana O. ; Deng, Lu ; Kasper, Brian ; Sood, Amika ; Paschal, Beth M. ; Zhang, Ping ; Ling, Chang Chun ; Klassen, John S. ; Noren, Christopher J. ; Mahal, Lara ; Woods, Robert J. ; Coates, Leighton ; Derda, Ratmir. / Genetically encoded fragment-based discovery of glycopeptide ligands for carbohydrate-binding proteins. In: Journal of the American Chemical Society. 2015 ; Vol. 137, No. 16. pp. 5248-5251.
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