In nature, specific antibodies can be generated as a result of an adaptive selection and expansion of lymphocytes with suitable protein binding properties. We attempted to mimic antibody–antigen recognition by displaying multiple chemical diversity elements on a defined macrocyclic scaffold. Encoding of the displayed combinations was achieved using distinctive DNA tags, resulting in a library size of 35,393,112. Specific binders could be isolated against a variety of proteins, including carbonic anhydrase IX, horseradish peroxidase, tankyrase 1, human serum albumin, alpha-1 acid glycoprotein, calmodulin, prostate-specific antigen and tumour necrosis factor. Similar to antibodies, the encoded display of multiple chemical elements on a constant scaffold enabled practical applications, such as fluorescence microscopy procedures or the selective in vivo delivery of payloads to tumours. Furthermore, the versatile structure of the scaffold facilitated the generation of protein-specific chemical probes, as illustrated by photo-crosslinking.
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This work was supported by ETH Zürich, the Swiss National Science Foundation (310030B_163479/1 grant, 31003A_144242 grant and CRSII2_160699/1 Sinergia grant), the ERC Advanced Grant ‘Zauberkugel’ (Grant agreement 670603), Philochem AG and through Start-up Funding for the ‘Hundred Young-Talent Scheme’ Professorship provided by Chongqing University in China (0247001104406). The authors thank G. Annuziato for help with synthesis, C. Aquino and L. Optiz for help with high-throughput DNA sequencing, and M. Wichert, R. Franzini, G. Zimmerman, A. Dal Corso, W. Decurtins, A. Schmid, L. Sun, M. Xi and J. Zhang for discussions. Instant JChem (ChemAxon) was used for structure and data management (http://www.chemaxon.com).
D.N. is a co-founder and shareholder of Philochem AG (Otelfingen, Switerland) and J.S. is a board member of Philochem AG.
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Li, Y., De Luca, R., Cazzamalli, S. et al. Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold. Nature Chem 10, 441–448 (2018). https://doi.org/10.1038/s41557-018-0017-8
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