Conformational and Electronic Variations in 1,2‐ and 1,5a‐Cyclophellitols and their Impact on Retaining α‐Glucosidase Inhibition

Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism‐based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol,...

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Published in:	Chemistry : a European journal Vol. 30; no. 31; pp. e202400723 - n/a
Main Authors:	Ofman, Tim P., Heming, Jurriaan J. A., Nin‐Hill, Alba, Küllmer, Florian, Moran, Elisha, Bennett, Megan, Steneker, Roy, Klein, Anne‐Mei, Ruijgrok, Gijs, Kok, Ken, Armstrong, Zach W. B., Aerts, Johannes M. F. G., Marel, Gijsbert A., Rovira, Carme, Davies, Gideon J., Artola, Marta, Codée, Jeroen D. C., Overkleeft, Herman S.
Format:	Journal Article
Language:	English
Published:	Germany Wiley Subscription Services, Inc 03-06-2024
Subjects:	alpha-Glucosidases - chemistry alpha-Glucosidases - metabolism Biological activity Carbasugar Conformational Analysis Congeners Covalence Cyclohexanols Cyclophellitol Density Functional Theory Glucosidase Glycosidases Glycoside hydrolase Glycoside Hydrolase Inhibitors - chemical synthesis Glycoside Hydrolase Inhibitors - chemistry Glycoside Hydrolase Inhibitors - pharmacology Humans Inhibitor Inhibitors Mode of action Molecular Conformation Natural products Structure-Activity Relationship Structure-function relationships Therapeutic targets Conformational Analysis Cyclophellitol Glucosidase Inhibitor Carbasugar
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Summary:	Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism‐based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism‐based, covalent and irreversible retaining β‐glucosidase inhibitor has inspired the design of diverse α‐ and β‐glycosidase inhibitor and activity‐based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol‐type compounds for effective human α‐glucosidase inhibition. We synthesized a comprehensive set of α‐configured 1,2‐ and 1,5a‐cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining α‐glucosidases. These studies revealed the 1,5a‐cyclophellitols to be the most potent retaining α‐glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non‐covalent). DFT calculations support the ability of the 1,5a‐cyclophellitols, but not the 1,2‐congeners, to adopt conformations that mimic either the Michaelis complex or transition state of α‐glucosidases. Twenty configurational and functional cyclophellitol analogues were synthesized and evaluated on their potency as retaining α‐glucosidase inhibitors. The inhibitory properties of the focused library of compounds were determined on human α‐glucosidases after which we mapped the conformational free energy landscapes of the most active compounds. Our results add to the growing list of covalent and competitive α‐glucosidase inhibitors and may pave the way towards the design of new therapeutics targeting these enzymes.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0947-6539 1521-3765 1521-3765
DOI:	10.1002/chem.202400723