TY  - JOUR
AU  - Visser, Emira J.
AU  - Jaishankar, Priyadarshini
AU  - Sijbesma, Eline
AU  - Pennings, Marloes A. M.
AU  - Vandenboorn, Edmee M. F.
AU  - Guillory, Xavier
AU  - Neitz, R. Jeffrey
AU  - Morrow, John
AU  - Dutta, Shubhankar
AU  - Renslo, Adam R.
AU  - Brunsveld, Luc
AU  - Arkin, Michelle R.
AU  - Ottmann, Christian
TI  - From Tethered to Freestanding Stabilizers of 14‐3‐3 Protein‐Protein Interactions through Fragment Linking
JO  - Angewandte Chemie
VL  - 62
IS  - 37
SN  - 1433-7851
CY  - Weinheim
PB  - Wiley-VCH
M1  - PUBDB-2023-07400
SP  - e202308004
PY  - 2023
AB  - Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.
LB  - PUB:(DE-HGF)16
C6  - pmid:37455289
UR  - <Go to ISI:>//WOS:001040530100001
DO  - DOI:10.1002/anie.202308004
UR  - https://bib-pubdb1.desy.de/record/599428
ER  -