Academic Journal
Deconstructing Best‐in‐Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase Inhibition
| العنوان: | Deconstructing Best‐in‐Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase Inhibition |
|---|---|
| المؤلفون: | Liang, Yan, Schettini, Rosaria, Kern, Nicolas, Manciocchi, Luca, Izzo, Irene, Spichty, Martin, Bodlenner, Anne, Compain, Philippe |
| المساهمون: | Laboratoire d'innovation moléculaire et applications (LIMA), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Salerno = University of Salerno (UNISA) |
| المصدر: | ISSN: 0947-6539. |
| بيانات النشر: | HAL CCSD Wiley-VCH Verlag |
| سنة النشر: | 2024 |
| المجموعة: | Archive ouverte HAL (Hyper Article en Ligne, CCSD - Centre pour la Communication Scientifique Directe) |
| مصطلحات موضوعية: | [CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry |
| الوصف: | International audience ; Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non‐polymeric glycosidase inhibitor have been obtained with cyclopeptoid‐based inhibitors of Jack bean α‐mannosidase (JBα‐man). Here, we report a structure‐activity relationship (SAR) study based on the top‐down deconstruction of best‐in‐class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate‐binding, resulting from the formation of a cross‐linked complex between a multivalent inhibitor and two dimeric JBα‐man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | hal-04410168; https://hal.science/hal-04410168; https://hal.science/hal-04410168/document; https://hal.science/hal-04410168/file/AcceptedManuscriptAutors.pdf |
| DOI: | 10.1002/chem.202304126 |
| الاتاحة: | https://hal.science/hal-04410168 https://hal.science/hal-04410168/document https://hal.science/hal-04410168/file/AcceptedManuscriptAutors.pdf https://doi.org/10.1002/chem.202304126 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.44E57047 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/chem.202304126 |
|---|