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Allylic Carbocyclic Inhibitors Covalently Bind Glycoside Hydrolases


Grayfer, Tatyana D; Yamani, Khalil; Jung, Erik; Chesnokov, Gleb A; Ferrara, Isabella; Hsiao, Chien-Chi; Georgiou, Antri; Michel, Jeremy; Bailly, Aurélien; Sieber, Simon; Eberl, Leo; Gademann, Karl (2023). Allylic Carbocyclic Inhibitors Covalently Bind Glycoside Hydrolases. JACS Au, 3(4):1151-1161.

Abstract

Allylic cyclitols were investigated as covalent inhibitors of glycoside hydrolases by chemical, enzymatic, proteomic, and computational methods. This approach was inspired by the C$_{7}$ cyclitol natural product streptol glucoside, which features a potential carbohydrate leaving group in the 4-position (carbohydrate numbering). To test this hypothesis, carbocyclic inhibitors with leaving groups in the 4- and 6- positions were prepared. The results of enzyme kinetics analyses demonstrated that dinitrophenyl ethers covalently inhibit α-glucosidases of the GH13 family without reactivation. The labeled enzyme was studied by proteomics, and the active site residue Asp214 was identified as modified. Additionally, computational studies, including enzyme homology modeling and density functional theory (DFT) calculations, further delineate the electronic and structural requirements for activity. This study demonstrates that previously unexplored 4- and 6-positions can be exploited for successful inhibitor design.

Abstract

Allylic cyclitols were investigated as covalent inhibitors of glycoside hydrolases by chemical, enzymatic, proteomic, and computational methods. This approach was inspired by the C$_{7}$ cyclitol natural product streptol glucoside, which features a potential carbohydrate leaving group in the 4-position (carbohydrate numbering). To test this hypothesis, carbocyclic inhibitors with leaving groups in the 4- and 6- positions were prepared. The results of enzyme kinetics analyses demonstrated that dinitrophenyl ethers covalently inhibit α-glucosidases of the GH13 family without reactivation. The labeled enzyme was studied by proteomics, and the active site residue Asp214 was identified as modified. Additionally, computational studies, including enzyme homology modeling and density functional theory (DFT) calculations, further delineate the electronic and structural requirements for activity. This study demonstrates that previously unexplored 4- and 6-positions can be exploited for successful inhibitor design.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
07 Faculty of Science > Department of Plant and Microbial Biology
07 Faculty of Science > Zurich-Basel Plant Science Center
Dewey Decimal Classification:580 Plants (Botany)
540 Chemistry
Scopus Subject Areas:Physical Sciences > Chemistry (miscellaneous)
Physical Sciences > Analytical Chemistry
Physical Sciences > Organic Chemistry
Physical Sciences > Physical and Theoretical Chemistry
Language:English
Date:24 April 2023
Deposited On:27 Jun 2023 11:55
Last Modified:29 Jun 2024 01:36
Publisher:American Chemical Society (ACS)
ISSN:2691-3704
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1021/jacsau.3c00037
PubMed ID:37124289
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)