Target‐Templated Construction of Functional Proteomimetics Using Photo‐Foldamer Libraries
Abstract 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
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1002/ange.202410435
- Citations
- 1
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Nemzeti Kutatási, Fejlesztési és Innovaciós Alap
- National Research, Development and Innovation Office