A Complementarity‐Based Approach to <i>De Novo</i> Binder Design
De novo design of binders capable of targeting arbitrarily selected epitopes remains a substantial challenge. Here, a generalizable computational strategy is presented to design site-specific protein binders, obviating steps of extensive empirical optimization or in vitro screening. The dock-and-design pipeline retrieves complementary scaffolds from a protein structure database to a given query epitope, where the scaffold is mutated to carve a binding site de novo. The docking step utilizes a novel fingerprint that greatly simplifies and accelerates the surface complementarity evaluation. As proof-of-concept, we designed protein binders to target three distinct epitopes on two different oncogenic targets; vascular endothelial growth factor (VEGF) and interleukin-7 receptor-α (IL-7Rα). Experimental characterization of only 24 candidates identified nanomolar binders against each of the target epitopes, where the binders belonged to five different folds. Several designs were active in vitro. Moreover, anti-VEGF designs showed tumor-inhibiting activity in vivo, highlighting their therapeutic potential.
Authors
- M.P. Coles (ORCID: https://orcid.org/0000-0001-6716-6150)
- Judith Feucht (ORCID: https://orcid.org/0000-0002-8745-1079)
- Matteo Pilz (ORCID: https://orcid.org/0000-0002-7470-0806)
- Kateryna Maksymenko (ORCID: https://orcid.org/0000-0002-0543-1323)
- Andrei N. Lupas (ORCID: https://orcid.org/0000-0002-1959-4836)
- Stefan Liebau (ORCID: https://orcid.org/0000-0003-0721-8187)
- Natalia Pashkovskaia (ORCID: https://orcid.org/0009-0002-0664-0845)
- Joana Pereira (ORCID: https://orcid.org/0000-0002-5588-6588)
- Julia Skokowa (ORCID: https://orcid.org/0000-0002-4399-2324)
- Narges Aghaallaei (ORCID: https://orcid.org/0000-0002-9890-3229)
- Marcus D. Hartmann (ORCID: https://orcid.org/0000-0001-6937-5677)
- Mohammad ElGamacy (ORCID: https://orcid.org/0000-0002-3446-8774)
- Patrick Müller (ORCID: https://orcid.org/0000-0002-0702-6209)
- Philip Bucher (ORCID: https://orcid.org/0000-0001-7951-1580)
- Natalia Borbarán‐Bravo
- Ghazaleh Tabatabai (ORCID: https://orcid.org/0000-0002-3542-8782)
- Valeriia Hatskovska
- Mareike Volz
Institutions
- University of Konstanz (DE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Max Planck Institute for Developmental Biology (DE)
- VIB-KU Leuven Center for Microbiology (BE)
- University Children's Hospital Tübingen (DE)
- Bernstein Center for Computational Neuroscience Tübingen (DE)
- Ludwig Boltzmann Institute Applied Diagnostics (AT)
- Hertie Institute for Clinical Brain Research (DE)
- Friedrich Miescher Laboratory (DE)
- Ludwig Boltzmann Institute for Cancer Research (AT)
- Max Planck Institute for Biology (DE)
- University of Tübingen (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-07-21
- DOI
- https://doi.org/10.1002/advs.202502015
- Citations
- 1
- Primary Topic
- Manufacturing Process and Optimization
- Type
- article
- Field-Weighted Citation Impact
- 1.24
Funders
- Deutsche Forschungsgemeinschaft
- Eberhard Karls Universität Tübingen
- Max-Planck-Gesellschaft
- José Carreras Leukämie-Stiftung
- HORIZON EUROPE Framework Programme
- HORIZON EUROPE European Research Council