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The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21

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Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2H-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is e.g. present in various bioactive natural products. Our investigations were focused on the compound MT-21 - a simplified structural analogue of the natural product epolactaene - which is known to have both neurotrophic activity and ability to trigger apoptotic cell death. We found that the central N-acyl hemiaminal group of MT-21 can function as an electrophilic centre enabling divergent reactivity with both amine- and thiol-based nucleophiles, which furthermore translated to reactivity with proteins in both cell lysates and live cells. We found that in live cells MT-21 strongly engaged the lipid transport protein fatty acid-binding protein 5 (FABP5) by direct binding to a cysteine residue in the bottom of the ligand binding pocket. Through preparation of a series of MT-21 derivatives, we probed the specificity of this interaction which was found to be strongly dependent on subtle structural changes. Our study suggests that MT-21 may be employed as a tool compound in future studies of the biology of FABP5, which remains incompletely understood. Furthermore, our study has also made clear that other natural products containing the AHPO-motif may likewise possess covalent reactivity and that this property may underlie their biological activity.

OriginalsprogEngelsk
TidsskriftRSC Chemical Biology
Vol/bind3
Nummer10
Sider (fra-til)1216-1229
Antal sider14
DOI
StatusUdgivet - 7 sep. 2022

Bibliografisk note

Funding Information:
Thanks to Prof. Daniel Otzen at the Interdisciplinary Nanoscience Center, Aarhus University, Denmark for use of circular dichorism spectrometer. Thanks to Prof. Karl Anker Jørgensen at the Department of Chemistry, Aarhus University, Denmark for use UPCC for chiral chromatography. TBP acknowleges support from the Carlsberg Foundation (grant CF17-800) and Novo Nordisk Foundation (grant NNF19OC0054782). YW and KLL were supported by the BRAINSTRUC initiative from the Lundbeck Foundation (R155-2015-2666). YW and KLL acknowledge access to computational resources from the Danish National Supercomputer for Life Sciences (Computerome) and the ROBUST Resource for Biomolecular Simulations (supported by the Novo Nordisk Foundation; NNF18OC0032608).

Publisher Copyright:
© 2022 RSC.

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