Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers

The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stab...

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Veröffentlicht in:	ACS medicinal chemistry letters Jg. 12; H. 6; S. 976
Hauptverfasser:	Sijbesma, Eline, Hallenbeck, Kenneth K, Andrei, Sebastian A, Rust, Reanne R, Adriaans, Joris M C, Brunsveld, Luc, Arkin, Michelle R, Ottmann, Christian
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	10.06.2021
ISSN:	1948-5875, 1948-5875
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Zusammenfassung:	The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1948-5875 1948-5875
DOI:	10.1021/acsmedchemlett.1c00088