Evidence map›Paper›PMID 41414041›Full record

ArticleAngewandte Chemie (International ed. in English)2026

Macrocyclic Molecular Glues for the 14-3-3/ChREBP Interaction: Affinity and Cooperativity in an Inverse Relationship.

Marloes A M Pennings, Merel A W van den Bosch, Ansgar Oberheide, Carlo J A Verhoef, Christian Ottmann, Albert J Markvoort, Galen P Miley, Luc Brunsveld

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Angewandte Chemie (International ed. in English), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Marloes A M PenningsLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0002-3366-0238
Merel A W van den BoschLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.
Ansgar OberheideLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0003-3664-5428
Carlo J A VerhoefLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0001-5720-1602
Christian OttmannLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0001-7315-0315
Albert J MarkvoortSynthetic Biology Group, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0001-6025-9557
Galen P MileyLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0003-4512-7913
Luc BrunsveldLaboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Eindhoven, 5600MB, The Netherlands.ORCID 0000-0001-5675-511X

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Molecular glues (MGs) stabilize protein-protein interactions (PPIs) by simultaneously binding two or more proteins at their composite interface. Macrocycles present attractive properties as MGs, including large contact surfaces to address the often flat and undefined composite PPI interfaces, but their structure-based design has remained intangible. We have designed peptidomimetic macrocycles capable of enhancing the PPI between 14-3-3 and the carbohydrate response element binding protein (ChREBP), a regulatory transcription factor. Biophysical characterization of these MGs revealed the importance of optimized linker length, displaying a reduced entropic cost compared to the linear counterparts, while preserving key contacts with 14-3-3. Binding assays demonstrated that the macrocycles selectively and cooperatively stabilized the 14-3-3/ChREBP complex, with an intriguing inverse relationship between intrinsic binding affinity to 14-3-3 and cooperativity in PPI stabilization. Ternary co-crystal structures of the macrocycles binding at the composite 14-3-3/ChREBP interface provided a molecular rationale for the affinity and cooperativity differences. Overall, this study highlights structural, kinetic, and thermodynamic features that guide effective macrocyclic MG design and brings forward the crucial interplay of affinity and cooperativity in stabilizing PPIs.

Indexed as

14-3-3 ProteinsMacrocyclic CompoundsTranscription FactorsHumansModels, MolecularProtein Binding14-3-3 ProteinsMacrocyclic CompoundsTranscription FactorsCooperativityMacrocycleMolecular glueProtein–protein interactionsStructural biology

Identifiers

PMID41414041
PMCPMC12865133

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.