Target‐Templated Construction of Functional Proteomimetics Using Photo‐Foldamer Libraries
Current methods for proteomimetic engineering rely on structure-based design. Here we describe a design strategy that allows the construction of proteomimetics against challenging targets without a priori characterization of the target surface. Our approach employs (i) a 100-membered photoreactive foldamer library, the members of which act as local surface mimetics, and (ii) the subsequent affinity maturation of the primary hits using systems chemistry. Two surface-oriented proteinogenic side chains drove the interactions between the short helical foldamer fragments and the proteins. Diazirine-based photo-crosslinking was applied to sensitively detect and localize binding even to shallow and dynamic patches on representatively difficult targets. Photo-foldamers identified functionally relevant protein interfaces, allosteric and previously unexplored targetable regions on the surface of STAT3 and an oncogenic K-Ras variant. Target-templated dynamic linking of foldamer hits resulted in two orders of magnitude affinity improvement in a single step. The dimeric K-Ras ligand mimicked protein-like catalytic functions. The photo-foldamer approach thus enables the highly efficient mapping of protein-protein interaction sites and provides a viable starting point for proteomimetic ligand development without a priori structural hypotheses.
Authors
- Elvin D. de Araujo (ORCID: https://orcid.org/0000-0003-0716-2830)
- Gábor Kecskeméti (ORCID: https://orcid.org/0000-0002-5584-6869)
- Péter Ábrányi‐Balogh (ORCID: https://orcid.org/0000-0002-9284-5160)
- Ferenc Bogár (ORCID: https://orcid.org/0000-0002-0611-1452)
- Attila Tököli (ORCID: https://orcid.org/0000-0001-8413-3182)
- György M. Keserű (ORCID: https://orcid.org/0000-0003-1039-7809)
- Dávid Bajusz (ORCID: https://orcid.org/0000-0003-4277-9481)
- Nikolett Péczka
- Éva Bartus (ORCID: https://orcid.org/0000-0001-9976-6978)
- Tamás Takács (ORCID: https://orcid.org/0000-0003-3321-8690)
- András Perczel (ORCID: https://orcid.org/0000-0003-1252-6416)
- Zoltán Orgován (ORCID: https://orcid.org/0000-0002-8002-3047)
- Dóra K. Menyhárd (ORCID: https://orcid.org/0000-0002-0095-5531)
- Zoltán Szabó (ORCID: https://orcid.org/0000-0001-8278-8038)
- Edit Wéber (ORCID: https://orcid.org/0000-0002-5904-0619)
- Tamás A. Martinek (ORCID: https://orcid.org/0000-0003-3168-8066)
- Gitta Schlosser (ORCID: https://orcid.org/0000-0002-7637-7133)
- László Buday (ORCID: https://orcid.org/0000-0003-3518-5757)
- Márton Gadanecz (ORCID: https://orcid.org/0009-0009-8076-7597)
- Gábor K. Tóth (ORCID: https://orcid.org/0000-0002-3604-4385)
- Tibor Viktor Szalai
- Bence Nagymihály
Institutions
- Eötvös Loránd University (HU)
- University of Toronto (CA)
- University of Szeged (HU)
- Budapest University of Technology and Economics (HU)
- HUN-REN Research Centre for Natural Sciences (HU)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1002/anie.202410435
- Citations
- 7
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
- National Research, Development and Innovation Office