Target‐templated Construction of Functional Proteomimetics Using Photo‐foldamer Libraries

Wéber, Edit and Ábrányi-Balogh, Péter and Nagymihály, Bence and Karancsiné Menyhárd, Dóra and Péczka, Nikolett and Gadanecz, Márton and Schlosser, Gitta (Vácziné) and Orgován, Zoltán and Bogár, Ferenc and Bajusz, Dávid and Kecskeméti, Gábor and Szabó, Zoltán and Bartus, Éva and Tököli, Attila and Tóth, Gábor and Szalai, Tibor V. and Takács, Tamás and de Araujo, Elvin and Buday, László and Perczel, András and Martinek, Tamás and Keserű, György Miklós (2025) Target‐templated Construction of Functional Proteomimetics Using Photo‐foldamer Libraries. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 64 (2). No.-e202410435. ISSN 1433-7851

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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 relies on (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 detected 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.

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