From Tethered to Freestanding Stabilizers of 14‐3‐3 Protein‐Protein Interactions through Fragment Linking

Author:

Visser Emira J.1,Jaishankar Priyadarshini2,Sijbesma Eline1,Pennings Marloes A. M.1,Vandenboorn Edmee M. F.1,Guillory Xavier1,Neitz R. Jeffrey2,Morrow John2,Dutta Shubhankar2,Renslo Adam R.2,Brunsveld Luc1,Arkin Michelle R.2,Ottmann Christian1ORCID

Affiliation:

1. Laboratory of Chemical Biology Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology Den Dolech 2 5612 AZ Eindhoven The Netherlands

2. Department of Pharmaceutical Chemistry and Small Molecule Discovery Centre (SMDC) University of California San Francisco (UCSF) San Francisco CA 94143 USA

Abstract

AbstractSmall‐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.

Funder

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Ono Pharma Foundation

Publisher

Wiley

Subject

General Medicine

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